Propanamine derivatives as serotonin and norepinephrine reuptake inhibitors

ABSTRACT

There is provided a heretoaryloxy/thio 3-substituted propanamine compound of formula (I) wherein A is selected from —)— and —S—; X is selected from phenyl optionally substituted with up to 5 substituents each independently selected from halo, C 1 -C 4  alkyl and C 1 -C 4  alkoxy, thienyl optionally substituted with up to 3 substituents each independently selected from halo and C 1 -C 4  alkyl, and C 2 -C 8  alkyl, C 2 -C 8  alkenyl, C 3 -C 8  cycloalkyl and C 4 -C 8  cycloalkylalkyl, each of which may be optionally substituted with up to 3 substituents each independently selected from halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, C 1 -C 4  alkyl —S(O) n — where n is 0, 1 or 2, —CF 3 , —CN and —CONH 2 ; Y is selected from dihydrobenzothienyl, benzothiazolyl, benzoisothiazolyl, quinolyl, isoquinolyl, naphthyridyl, and thienopyridyl, each of which may be optionally substituted with up to 4 or, where possible, up to 5 substituents each independently selected from halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, C 1 -C 4  alkyl-S(O) n — where n is  0, 1  or  2 , nitro acetyl, —CF 3 , —SCF 3  and cyano; Z is selected from H, OR 3  or F, wherein R 3  is selected from H, C 1 -C 6  alkyl and phenyl C 1 C 6  alkyl; R 1  and R 2  are each independently H or C 1 -C 4  alkyl; and pharmaceutically acceptable salts thereof.

This invention relates to novel heteroaryloxy/thio 3-substitutedpropanamines, and to their use in inhibiting serotonin andnorepinephrine reuptake.

Serotonin (5-HT) has been implicated in the aetiology of many diseasestates and has been found to be of importance in mental illnesses,depression, anxiety, schizophrenia, eating disorders, obsessivecompulsive disorder (OCD) and migraine. Indeed many currently usedtreatments of these disorders are thought to act by modulatingserotonergic tone. During the last decade, multiple serotonin receptorsubtypes have been characterised. This has led to the realisation thatmany treatments act via the serotonergic system, such as selectiveserotonin reuptake inhibitor (SSRI) antidepressants which increaseserotonin transmission, such as, for example, the hydrochloride salt offluoxetine.

Drugs that exert their main action on the norepinephrinergic system havebeen available for some time, however their lack of selectivity made itdifficult to determine specific clinical effects produced by a selectiveaction on norepinephrine reuptake. Accumulating evidence indicates thatthe norepinephrinergic system modulates drive and energy, whereas theserotonergic system modulates mood. Thus norepinephrine appears to playan important role in the disturbances of vegetative function associatedwith affective, anxiety and cognitive disorders. Atomoxetinehydrochloride is a selective inhibitor of norepinephrine, and iscurrently marketed for the treatment of attention deficit hyperactivitydisorder (ADHD).

Norepinephrine and serotonin receptors are known to interactanatomically and pharmacologically. Compounds that affect only serotoninhave been shown to exhibit modulatory effects on norepinephrine,pointing toward an important relationship between the twoneurotransmitter systems.

Duloxetine, (+)-N-methyl-3-(1-naphthalenyloxy)-2-thiophenepropanaminehydrochloride, inhibits the reuptake of both norepinephrine andserotonin, and is currently under development for the treatment ofdepression and urinary incontinence. The compound duloxetine wasdisclosed in U.S. Pat. Nos. 5,023,269 and 4,956,388.

U.S. Pat. No. 4,018,895 describes aryloxyphenyl propanamine compoundsincluding compunds of the formula

Where R is, for example, phenyl, substituted phenyl, tolyl or anisyl.The compounds block the uptake of various physiologically activemonoamines including serotonin, norepinephrine and dopamine. Some of thecompounds are selective to one of the monoamines and others havemultiple activity. The compounds are indicated as psychotropic agents.Some are also antagonists of apomorphine and/or reserpine.

WO 00/02551 describes inter alia 3-aryloxy-3-substituted propanamineswhich are active at the NMDA receptor and serotonin reuptake site.

WO 97/45115 describes compounds which inhibit glycine transport via theGlyT-1 or GlyT-2 transporters. Some of the compounds disclosed are3-aryloxy-3-phenyl-substituted propanamines although they also possessfurther N-substitution by, for example, CH2(CO2)Et.

EP 0318727 and EP 0399504 disclose certain aryloxyphenylpropanamines foruse as calcium antagonists.

WO 01/62714 discloses phenylheteroalkylamine derivatives which areinhibitors of nitric oxide synthase. WO 03/011831 and WO 03/011830discloses heteroarylheteroalkylamine derivatives which are inhibitors ofnitric oxide synthase.

WO 02/094262 discloses heteroaryloxy 3-substituted propanamines asserotonin and norepinephrine reuptake inhibitors.

The present invention provides novel heteroaryloxy/thio propanamineswhich are potent inhibitors of both serotonin and norepinephrinereuptake. Preferred compounds of the present invention exihibit (i)greater potency of inhibition of the serotonin and/or morepinephrinetransporters; and/or (ii) improved selectivity of inhibition of theserotonin and/or norepinephrine transporters relative to the dopaminetransporter, and/or (iii) improved ADME properties (e.g. reducedtendency to act as a substrate and/or inhibitor the enzyme CytochromeP450 2D6), and/or (iv) improved acid stability, as compared knowninhibitors of both serotonin and norepinephrine reuptake.

According to the present invention there is provided a compound offormula I:

wherein

A is selected from —O— and —S—;

X is selected from

phenyl optionally substituted with up to 5 substituents eachindependently selected from halo, C₁-C₄ alkyl and C₁-C₄ alkoxy,

thienyl optionally substituted with up to 3 substituents eachindependently selected from halo and C₁-C₄ alkyl, and

C₂-C₈ alkyl, C₂-C₈ alkenyl, C₃-C₈ cycloalkyl and C₄-C₈ cycloalkylalkyl,each of which may be optionally substituted with up to 3 substituentseach independently selected from halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄alkyl-S(O)_(n)— where n is 0, 1 or 2, —CF₃, —CN and —CONH₂;

Y is selected from dihydrobenzothienyl, benzothiazolyl,benzoisothiazolyl, quinolyl, isoquinolyl, naphthyridyl, andthienopyridyl, each of which may be optionally substituted with up to 4or, where possible, up to 5 substituents each independently selectedfrom halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ alkyl-S(O)_(n)— where n is0, 1 or 2, nitro, acetyl, —CF₃, —SCF₃ and cyano;

Z is selected from H, OR₃ or F, wherein R₃ is selected from H, C₁-C₆alkyl and phenyl C₁-C₆ alkyl;

R₁ and R₂ are each independently H or C₁-C₄ alkyl; and pharmaceuticallyacceptable salts thereof.

The compounds of the present invention are potent and selectiveinhibitors of serotonin and norepinephrine reuptake.

In one group of compounds according to the present invention, A is —O—.

In another group of compounds according to the present invention, A is—S—.

Preferably, one of R₁ and R₂ is H.

R₁ and R₂ may both be H. Alternatively, one of R₁ and R₂ may be H whilethe other is C₁-C₄ alkyl, for example C₁-C₃ alkyl. Preferably, one of R₁and R₂ is H and the other is methyl.

It will be appreciated that a compound of formula I will possess atleast one or, when Z is not H, at least two chiral centres. Where astructural formula does not specify the stereochemistry at one or morechiral centres, it encompasses all possible stereoisomers and allpossible mixtures of stereoisomers (including, but not limited to,racemic mixtures) which may result from stereoisomerism at each of theone or more chiral centers.

In one embodiment of the present invention, the compound possesses thestereochemistry defined in formula II

In another embodiment of the present invention, the compound possessesthe stereochemistry defined in formula III

In another embodiment of the present invention, Z is H.

In one embodiment of the present invention, X is unsubstituted phenyl orphenyl which is mono- di- or tri-substituted with substituentsindependently selected from halo, C₁-C₄ alkyl and/or C₁-C₄ alkoxy. Halosubstituents include P, Cl, Br and I, preferably F or Cl. Preferably, Xis unsubstituted phenyl or phenyl which is mono-substituted withfluorine.

When X in formula I above is substituted thienyl, it is preferablymono-, di- or tri-substituted. Halo substituents include F, Cl, Br andI, preferably F or Cl. Suitable C₁-C₄ alkyl substituents includeunsubstituted straight or branched alkyl groups of 1, 2, 3 or 4 carbonatoms, preferably methyl. When X is thienyl it is preferably thien-2-yl.

In one embodiment of the present invention, Y is dihydrobenzothienyloptionally substituted with up to 5 substituents each independentlyselected from halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ alkyl-S(O)_(n)—where n is 0, 1 or 2, nitro, acetyl, —CF₃, —SCF₃ and cyano. In thisembodiment, Y is preferably unsubstituted dihydrobenzothienyl ordihydrobenzothienyl which is mono-substituted with fluorine, preferablyat the 4-position.

In one embodiment of the present invention, Y is benzothiazolyl orbenzoisothiazolyl, each of which may be optionally substituted with upto 4 substituents each independently selected from halo, C₁-C₄ alkyl,C₁-C₄ alkoxy, C₁-C₄ alkyl-S(O)_(n)— where n is 0, 1 or 2, nitro, acetyl,—CF₃, —SCF₃ and cyano. In this embodiment, Y is preferably unsubstitutedbenzothiazolyl, unsubstituted benzoisothiazolyl, benzothiazolyl which ismono-substituted with CH₃ (preferably in the 4- or 7-position) orbenzoisothiazolyl which is mono-substituted with CH₃ (preferably in the4- or 7-position).

In one embodiment of the present invention, Y is thienopyridyloptionally substituted with up to 4 substituents each independentlyselected from halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ alkyl-S(O)_(n)—where n is 0, 1 or 2, nitro, acetyl, —CF₃, —SCF₃ and cyano. In thisembodiment, Y is preferably unsubstituted thienopyridyl, more preferablyselected from thieno-[2,3-b]pyridinyl, thieno-[2,3-c]pyridinyl,thieno-[3,2-c]pyridinyl and thieno-[3,2-b]pyridinyl withthieno-[3,2-b]pyridinyl and thieno-[3,2-c]pyridinyl being mostpreferred.

In the embodiments described above wherein Y is dihydrobenzothienyl,benzothiazolyl, benzoisothiazolyl or thienopyridyl, each of which beingoptionally substituted as described above, the preferred point ofattachment of the group Y to the —O— or —S— atom is attachment at the 4or 7 position.

In one embodiment of the present invention, Y is quinolyl, isoquinolylor naphthyridyl, each of which may be optionally substituted with up to5 substituents each independently selected from halo, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ alkyl-S(O)_(n)— where n is 0, 1 or 2, nitro, acetyl, —CF₃,—SCF₃ and cyano. In this embodiment, Y is preferably unsubstitutedquinolyl, isoquinolyl or naphthyridyl. When Y is unsubstitutednaphthyridyl it is preferably selected from 1,5-, 1,6-, 1,7- and1,8-naphthyridyl with 1,7-naphthyridyl being most preferred.

In the embodiments described above wherein Y is quinolyl, isoquinolyl ornaphthyridyl, the preferred point of attachment of the group Y to the—O— or —S— atom is attachment at the 4, 5 or 6 position.

The present invention also provides sub-groups of compounds of formula Ior II or III:

wherein

A is selected from —O— and —S—;

X is selected from

phenyl optionally substituted with up to 5 substituents eachindependently selected from halo, C₁-C₄ alkyl and C₁-C₄ alkoxy, and

thienyl optionally substituted with up to 3 substituents eachindependently selected from halo and C₁-C₄ alkyl;

Y is selected from dihydrobenzothienyl, benzothiazolyl,benzoisothiazolyl, quinolyl, isoquinolyl, naphthyridyl, andthienopyridyl, each of which may be optionally substituted with up to 4or, where possible, up to 5 substituents each independently selectedfrom halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ alkyl-S(O)_(n)— where n is0, 1 or 2, nitro, acetyl, —CF₃, —SCF₃ and cyano;

Z is selected from H, OR₃ or F, wherein R₃ is selected from H, C₁-C₆alkyl and phenyl C₁-C₆ alkyl;

R₁ and R₂ are each independently H or C₁-C₄ alkyl;

and pharmaceutically acceptable salts thereof.

The present invention also provides sub-groups of compounds of formula Ior II or III:

wherein

A is selected from —O— and —S—;

X is selected from

phenyl optionally substituted with up to 5 substituents eachindependently selected from halo, C₁-C₄ alkyl and C₁-C₄ alkoxy, and

thienyl optionally substituted with up to 3 substituents eachindependently selected from halo and C₁-C₄ alkyl;

Y is selected from dihydrobenzothienyl, benzothiazolyl,benzoisothiazolyl, quinolyl, isoquinolyl, naphthyridyl, andthienopyridyl, each of which may be optionally substituted with up to 4or, where possible, up to 5 substituents each independently selectedfrom halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ alkyl-S(O)n- where n is 0, 1or 2, nitro, acetyl, —CF₃, —SCF₃ and cyano;

Z is H;

R₁ and R₂ are each independently H or C₁-C₄ alkyl;

and pharmaceutically acceptable salts thereof.

The present invention also provides sub-groups of compounds of formula Ior II or III:

wherein

A is selected from —O— and —S—;

X is phenyl optionally substituted with up to 5 substituents eachindependently selected from halo, C₁-C₄ alkyl and C₁-C₄ alkoxy;

Y is selected from dihydrobenzothienyl, benzothiazolyl,benzoisothiazolyl, quinolyl, isoquinolyl, naphthyridyl, andthienopyridyl, each of which may be optionally substituted with up to 4or, where possible, up to 5 substituents each independently selectedfrom halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ alkyl-S(O)n- where n is 0, 1or 2, nitro, acetyl, —CF₃, —SCF₃ and cyano;

Z is H;

R₁ and R₂ are each independently H or C₁-C₄ alkyl;

and pharmaceutically acceptable salts thereof.

-   -   present invention also provides sub-groups of compounds of        formula I or II or III:        wherein    -   A is —O—;

X is phenyl optionally substituted with up to 5 substituents eachindependently selected from halo, C₁-C₄ alkyl and C₁-C₄ alkoxy;

Y is selected from dihydrobenzothienyl, benzothiazolyl,benzoisothiazolyl, quinolyl, isoquinolyl, naphthyridyl, andthienopyridyl, each of which may be optionally mono-substituted withhalo, C₁-C₄ alkyl, C₁-C₄ alkoxy, -CF₃, or cyano;

Z is H;

R₁ and R₂ are each independently H or C₁-C₄ alkyl;

and pharmaceutically acceptable salts thereof.

The present invention also provides sub-groups of compounds of formula Ior II or III:

wherein

A is —O—;

X is phenyl optionally mono-substituted with fluorine;

Y is selected from dihydrobenzothienyl, benzothiazolyl,benzoisothiazolyl, quinolyl, isoquinolyl, naphthyridyl, andthienopyridyl, each of which may be optionally mono-substituted withfluoro or methyl;

Z is H;

R₁ is H and R₂ is methyl;

and pharmaceutically acceptable salts thereof.

In the present specification the term “C₂-C₈ alkyl” means a monovalentunsubstituted saturated straight-chain or branched-chain hydrocarbonradical having from 2 to 8 carbon atoms.

In the present specification the term “C₂-C₈ alkenyl” means a monovalentunsubstituted unsaturated straight-chain or branched-chain hydrocarbonradical having from 2 to 8 carbon atoms.

In the present specification the term “C₃-C₈ cycloalkyl” means amonovalent unsubstituted saturated cyclic hydrocarbon radical havingfrom 3 to 8 carbon atoms.

In the present specification the term “C₄-C₈ cycloalkylalkyl” means amonovalent unsubstituted saturated cyclic hydrocarbon radical havingfrom 3 to 7 carbon atoms linked to the point of substitution by adivalent unsubstituted saturated straight-chain or branched-chainhydrocarbon radical having at least 1 carbon atom.

In the present specification the term “halo” or “halogen” means F, Cl,Br or I.

In the present specification the term “C₁-C₄ alkoxy” means a monovalentunsubstituted saturated straight-chain or branched-chain hydrocarbonradical having from 1 to 4 carbon atoms linked to the point ofsubstitution by an O atom.

In the present specification the term “phenyl C₁-C₆ alkyl” means amonovalent phenyl radical linked to the point of substitution by adivalent unsubstituted saturated straight-chain or branched-chainhydrocarbon radical having from 1 to 6 carbon atoms.

In the above definitions, similar terms specifying different numbers ofC atoms take an analogous meaning.

In the present specification the term “dihydrobenzothienyl” includes2,3-dihydrobenzothienyl and 1,3-dihydrobenzothienyl.2,3-dihydrobenzothienyl is preferred.

In the present specification the term “benzoisothiazolyl” includes1,2-benzoisothiazolyl and 2,1-benzoisothiazolyl. 1,2-benzoisothiazolylis preferred.

In the present specification the term “naphthyridyl” includes 1,5-,1,6-, 1,7- and 1,8-naphthyridyl. 1,7- naphthyridyl is preferred.

In the present specification the term “thienopyridyl” includesthieno-[2,3-b]pyridinyl, thieno-[2,3-c]pyridinyl,thieno-[3,2-c]pyridinyl and thieno-[3,2-b]pyridinyl.Thieno-[3,2-b]pyridinyl and thieno-[3,2-c]pyridinyl are preferred.

In the present specification the abbreviation “Ace-Cl” stands forα-chloroethyl chloroformate.

In the present specification the abbreviation “PS-DIPEA” stands forpolymer-supported diisopropylethylamine.

The present invention also provides a process for producing a compoundof formula I above, or a pharmaceutically acceptable salt thereof, whichcomprises reacting a compound of the formula IV:

where A, X, Y and Z are as formula I above, and W is a leaving group,with an amine NR₁R₂ where R₁ and R₂ are as formula I above, optionallyfollowed by the step of forming a pharmaceutically acceptable salt.Examples of suitable leaving groups include halo, mesylate and tosylate,but the nature of the leaving group is not critical. The reaction may becarried out in a sealed vessel with a lower alkyl alcohol as solvent.

The present invention also provides a process for producing a compoundof formula I above wherein R₂ is H, or a pharmaceutically acceptablesalt thereof, which comprises deprotecting a compound of the formula V

where A, X, Y, Z and R₁ are as formula I above, and R₄ is a suitableN-protecting group, optionally followed by the step of forming apharmaceutically acceptable salt. Examples of suitable N-protectinggroups will be known to the person skilled in the art and include, forexample, benzyl and t-butoxycarbonyl.

The present invention also provides a process for producing a compoundof formula I above wherein Z is OH, or a pharmaceutically acceptablesalt thereof, which comprises reacting a compound of the formula VI

where A, X and Y are as formula I above with an amine NR₁R₂ where R₁ andR₂ as as formula I above, optionally followed by the step of forming apharmaceutically acceptable salt.

The present invention also provides a process for producing a compoundof formula I above wherein R₁ and R₂ are H, or a pharmaceuticallyacceptable salt thereof, which comprises reducing a compound of theformula VII:

where A, X, Y and Z are as formula I above, optionally followed by thestep of forming a pharmaceutically acceptable salt. Examples of suitablereducing agents will be known to the person skilled in the art.

The present invention also provides a process for producing a compoundof formula I above wherein R₁ and R₂ are C₁-C₄ alkyl, or apharmaceutically acceptable salt thereof, which comprises N-protecting acompound of the formula VIII by the introduction of two C₁C₄ alkylgroups:

where A, X, Y and Z are as formula I above, optionally followed by thestep of forming a pharmaceutically acceptable salt. Examples of suitablereagents for effecting N-protection by two C₁- C₄ alkyl groups will beknown to the person skilled in the art.

Compounds of the present invention are selective inhibitors of thereuptake of both serotonin and norepinephrine and as such are useful aspharmaceuticals. They are particularly useful for the treatment of pain.

For clinical purposes, pain may be divided into two categories: acutepain and persistent pain. Acute pain is provoked by noxious stimulationproduced by injury and/or disease of skin, deep somatic structures orviscera, or abnormal function of muscle or viscera that does not produceactual tissue damage. On the other hand, persistent pain can be definedas pain that persists beyond the usual course of an acute disease or areasonable time for an injury to heal or that is associated with achronic pathologic process that causes continuous pain or the painrecurs at intervals for months or years. If pain is still present aftera cure should have been achieved, it is considered persistent pain. Forthe purpose of the present invention, persistent pain can be chronicnon-remitting or recurrent. The difference in definition between acuteand persistent pain is not merely semantic but has an important clinicalrelevance. For example, a simple fracture of the wrist usually remainspainful for a week to 10 days. If the pain is still present beyond thetypical course of treatment, it is likely that the patient is developingreflex sympathetic dystrophy, a persistent pain syndrome that requiresimmediate effective therapy. Early and effective interventionpotentially prevents the undue disability and suffering, and avoids thepotential development of a condition that becomes refractory to therapy.

Acute and chronic pain differ in etiology, mechanisms, pathophysiology,symptomatology, diagnosis, therapy, and physiological responses. Incontrast to the transitory nature of acute pain, persistent pain iscaused by chronic pathologic processes in somatic structures or viscera,by prolonged and sometimes permanent dysfunction of the peripheral orcentral nervous system, or both. Also, persistent pain can sometimes beattributed to psychologic mechanisms and/or environmental factors.

Current therapies for persistent pain include opiates, barbiturate-likedrugs such as thiopental sodium and surgical procedures such asneurectomy, rhizotomy, cordotomy, and cordectomy.

The compounds of the present invention are indicated in the treatment ofpersistent pain and references herein to pain are intended to refer topersistent pain.

In addition to the compounds of formula I and processes for thepreparation of said compounds, the present invention further providespharmaceutical compositions comprising a compound of formula I or apharmaceutically acceptable salt thereof, together with apharmaceutically acceptable diluent or carrier.

Further, the present invention provides a compound of formula I or apharmaceutically acceptable salt thereof, for use as a pharmaceutical;and a compound of formula I or a pharmaceutically acceptable saltthereof, for use as a selective inhibitor of the reuptake of bothserotonin and norepinephrine.

The present compounds and salts may be indicated in the treatment ofdisorders associated with serotonin and norepinephrine dysfunction inmammals.

The term “serotonin and norepinephrine dysfunction” as used hereinrefers to a reduction in the amount of serotonin and norepinephrineneurotransmitters within the synaptic cleft below that which would beconsidered to be normal or desirable for a species, or an individualwithin that species. Thus the phrase “disorders associated withserotonin and norepinephrine dysfunction in mammals” refers to disorderswhich are associated with a reduction in the amount of serotonin andnorepinephrine neurotransmitters within the synaptic cleft below thatwhich would be considered to be normal or desirable for the mammalianspecies, or an individual within the species, in question. Some examplesof disorders currently believed to be associated with reduced levels ofserotonin and norepinephrine within the synaptic cleft includedepression, OCD, anxiety, memory loss, urinary incontinence (includingstress urinary incontinence and urge incontinence), conduct disorders,attention-deficit disorder (including ADHD), obesity, hotflushes/flashes, pain (including inflammatory pain, neuropathic pain,non-neuropathic non-inflammnatory pain, persistent pain, persistent painof inflammatory and/or neuropathic origin, headache and migraine),eating disorders (including bulimia and anorexia nervosa), inflammatorybowel disorders, functional bowel disorders, dyspepsia, chron's disease,iletis, ischemic bowel disease, ulcerative colitis, gastroesophagealreflux for functional bowel disorders, irritable bowel syndrome,insterstitial cystitis, urethral syndrome, gastric motility disorders,substance abuse (including alcoholism, tobacco abuse, smoking cessation,symptoms caused by withdrawal or partial withdrawal from the use oftobacco or nicotine and drug addiction including cocaine abuse),dementia of ageing, senile dementia, Alzheimer's, Parkinsonism, socialphobia, disruptive behavior disorders, impulsive control disorders,borderline personality disorder, chronic fatigue syndrome, panicdisorders, post-traumatic stress disorder, schizophrenia,gastrointestinal disorders, cardiovascular disorders, emesis, sleepdisorders, cognitive disorders, psychotic disorders, brain trauma,premenstrual syndrome or late luteal syndrome, sexual dysfunction(including premature ejaculation and erectile difficulty), autism,mutism and trichotilomania. The compounds of the present invention areparticularly suitable for the treatment of pain.

The compounds of the present invention are also indicated for thetreatment of disorders which are ameliorated by an increase in theamount of serotonin and norepinephrine neurotransmitters within thesynaptic cleft of a mammal above that which would be considered to benormal or desirable for the mammalian species, or an individual withinthe species, in question.

The term “treatment” as used herein refers to both curative andprophylactic treatment of disorders associated with norepinephrinedysfunction.

The present invention also provides the use of a compound of formula I,or a pharmaceutically acceptable salt thereof, in the manufacture of amedicament for selectively inhibiting the reuptake of serotonin andnorepinephrine; the use of a compound of formula I, or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment of disorders associated with serotonin andnorepinephrine dysfunction in mammals; the use of a compound of formulaI, or a pharmaceutically acceptable salt thereof, in the manufacture ofa medicament for the treatment of a disorder selected from those listedabove and in particular selected from depression, OCD, anxiety, memoryloss, urinary incontinence, conduct disorders, ADHD, obesity,alcoholism, smoking cessation, hot flushes/flashes and pain; and the useof a compound of formula I, or a pharmaceutically acceptable saltthereof, in the manufacture of a medicament for the treatment of adisorder selected from depression, urinary incontinence, particularlystress induced urinary incontinence, and more especially, pain. Thepresent invention further provides a compound of formula I for treatingdisorders associated with serotonin and norepinephrine dysfunction inmammals, for example a disorder selected from those listed above and inparticular selected from depression, OCD, anxiety, memory loss, urinaryincontinence, conduct disorders, ADHD, obesity, alcoholism, smokingcessation, hot flushes/flashes and pain, especially depression, urinaryincontinence, particularly stress induced urinary incontinence, and,more especially, pain.

Further the present invention provides a method for selectivelyinhibiting the reuptake of serotonin and norepinephrine in mammals,comprising administering to a patient in need thereof an effectiveamount of a compound of formula I or a pharmaceutically acceptable saltthereof; a method for treating disorders associated with serotonin andnorepinephrine dysfunction in mammals, comprising administering to apatient in need thereof an effective amount of a compound of formula Ior a pharmaceutically acceptable salt thereof; and a method for treatinga disorder selected from those listed above and in particular selectedfrom depression, OCD, anxiety, memory loss, urinary incontinence,conduct disorders, ADHD, obesity, alcoholism, smoking cessation, hotflushes/flashes and pain, comprising administering to a patient in needthereof an effective amount of a compound of formula I or apharmaceutically acceptable salt thereof.

The present invention includes the pharmaceutically acceptable salts ofthe compounds of formula L Suitable salts include acid addition salts,including salts formed with inorganic acids, for example hydrochloric,hydrobromic, nitric, sulphuric or phosphoric acids, or with organicacids, such as organic carboxylic acids, for example pyruvic,lactobionic, glycolic, oxalic, maleic, hydroxymaleic, fumaric, malic,tartaric, citric, salicylic, o-acetoxybenzoic, or organic sulphonic,2-hydroxyethane sulphonic, toluene-p-sulphonic, bisethanesulphonic acidor methanesulphonic acid.

In addition to the pharmaceutically acceptable salts, other salts areincluded in the invention. They may serve as intermediates in thepurification of compounds or in the preparation of other, for examplepharmaceutically acceptable, acid addition salts, or are useful foridentification, characterisation or purification.

While all the compounds of the present invention are believed to inhibitthe reuptake of serotonin and norepinephrine in mammals there arecertain of these compounds which are preferred for such uses. Preferredvalues for A, X, Y, Z, R₁ and R₂ and substituents for each have been setout above.

Compounds of the present invention may be prepared by conventionalorganic chemistry techniques.

Where Z is H and X is phenyl the chiral alcohols are commerciallyavailable from the Aldrich Chemical Company in pure enantiomeric formand can be used without further purification. Additionally, thechloropropanols which are commercially available from the AldrichChemical Company may be converted via a Finkelstein reaction usingsodium iodide in acetone under reflux conditions to the correspondingiodopropanols and these may be used as an alternative to thechloropropanols.

Where Z is H and X is thienyl the corresponding thienyl-propanols cantypically be prepared generally as follows (W is as defined above):

Subjecting thiophene to classical Friedel-Crafts acylation with an acidchloride such as chloropropionyl chloride in roughly equal quantities,with a strong Lewis acid such as aluminium chloride in a non-proticsolvent such as dichloromethane or dichloroethane at temperaturesranging from −5° C. to reflux can result in the desired thienyl ketone.This ketone can be readily reduced to the desired alcohol eitherracemically using standard reducing agents such as sodium borohydride ina protic solvent such as the lower order alkyl alcohols, or Borane-THFcomplex in a polar non-protic solvent such as diethyl ether or THF.Chiral reduction of the ketone can be performed using a boron basedchiral reducing agent in which high enantiomeric excesses can beobtained. Further details regarding this procedure can be found in J.Labelled Compd. Rad., 1995, 36, (3), 213 and references therein.

Where Z is H and X is selected from C₂-C₈ alkyl, C₂-C₈ alkenyl, C₃-C₈cycloalkyl and C₄-C₈ cycloalkylalkyl, the corresponding 1-X,3-aminopropanols can be prepared via the corresponding3-amino-N-methoxy-N-methylpropanamide, known as a Weinreb amide, asfollows:

Subjecting a Weinreb amide of N-methyl β-alanine appropriately protectedat the nitrogen, for example as a t-butyl carbamate (Boc) or as a benzylamine, to an organometallic reagent like an alkyl Grignard or alkyllithium results in the desired X-substituted ketone. The ketone can bereadily reduced to the desired racemic alcohol using standard reducingagents such as sodium borohydride in a protic solvent such as lowerorder alkyl alcohols.

The Weinreb amides of this invention may be prepared by conventionalorganic chemistry techniques as exemplified below:

Subjecting a commercially available appropriately N-protected β-alanineto sodium hydride followed by methyl iodide results in the N-methylatedderivative, which then can be converted to the Weinreb amide by reactionwith N-methyl-O-methylhydroxylamine. The Weinreb amides can also beprepared by reacting a 3-bromopropanoyl chloride withN-methyl-O-methylhydroxylamine to give the Weinreb amide of3-bromopropanoic acid, which then can be substituted with anappropriately substituted amine to give the desired Weinreb amide.

Another preferred route to 1-X, 3-aminopropanols is addition of asuitable organometallic reagent to an appropriately N-protectedaminoaldehyde. Thus an appropriately protected amine can be added to avinyl aldehyde in a Michael addition reaction to give a 3-aminoaldehyde.The aminoaldehyde can be subjected to (for example) an alkyl Grignardreagent or an alkyl lithium reagent to give the desired 1-alkylpropanol.Selection of other Grignard reagents or organolithium reagents couldprovide other 1-X,3-aminopropanols.

Where Z is H and X is phenyl or thienyl, the corresponding ethers andthioethers can typically be prepared generally as follows (W, X, A and Yare as defined above).

The chiral hydroxy intermediates are subjected to arylation reactions.Various arylation conditions can be used such as the Mitsunobu reaction,wherein roughly equal quantities of the heteroaryl alcohol andchloropropanol or iodopropanol are stirred at temperatures of between 0°C. and reflux in a polar non-protic solvent such as THF, with acomplexing agent such as diethyl azodicarboxylate, or other derivativewith a phosphine ligand such as triphenylphosphine. Alternatively4,4-(dimethyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)-triphenylphosphonium in THF or toluene may be used in place of mixtures diethylazodicarboxylate and triphenylphosphine. This type of reaction is wellknown and further combinations of the Mitsunobu reagents can be found inOrganic Preparations and Procedures Int., 1996, 28, 2, 165 andreferences therein. Note however that for converting hydroxy to arylsulfide it is preferred to react the propanol species with Y—SH,(cyanomethyl)trimethylphosphonium iodide (Tetrahedron, 2001, 57,5451-5454) and diisopropylamine in propionitrile.

The corresponding ethers and thioethers can be readily converted to theamines by heating in a sealed vessel with the appropriate amine in alower alkyl alcohol solvent, at temperatures between 100° C. and 150° C.for between 1 and 6 hours. To aid handling of the resulting amines theirorganic acid salts can typically be prepared using equimolar quantitiesof the propanolamines with an organic acid such as oxalic and maleicacid. The reactants are generally combined in a mutual solvent such asethyl acetate, and the salt normally precipitates out over time and canbe isolated by filtration, or by removing the solvent in vacuo,re-dissolving in purified water and freeze drying to obtain the salt.

Where Z is H and X is C₂-C₈ alkyl, C₂-C₈ alkenyl, C₃-C₈ cycloalkyl orC₄-C₈ cycloalkylalkyl the corresponding ethers and thioethers cantypically be prepared under arylation conditions as described above.Deprotection of the amine group provides the compounds of the invention.

The following methodology applies where Z is OH and X is phenyl, C₂-C₈alkyl, C₂-C₈ alkenyl, C₃-C₈ cycloalkyl or C₄-C₈ cycloalkylalkyl.

The “anti” chain hydroxylated propanamines may be prepared using themethodology outlined below. Although X is shown as optionallysubstituted phenyl in the reaction schemes below, the same methodologycould be applied for other identities of X (except thienyl).

The “syn” chain hydroxylated propanamines may be prepared using themethod outlined below (conversion of (I) to (I) is further described inTetrahedron Let. 1986, 41, 4987). Although X is shown as phenyl in thereaction schemes below, the same methodology could be applied for otheridentities of X (except thienyl).

Alternatively, the “syn” chain hydroxylated propanamines, may beprepared using the method outlined below.

Alternatively, the “syn” and “anti” chain hydroxylated propanamines maybe prepared using the intermediates shown below.

The same chemical transformations may be applied to each intermediate toobtain each of the four stereochemically distinct final products. Forexample:

Starting from the other three intermediates, the same chemistry may beused to obtain the other three final products, i.e.

The four intermediates may be synthesized by two different routes. Thefirst route is shown below:

The other two intermediates may be obtained using the same chemistry butstarting with the compound:

The second route is shown below:

The other two intermediates may be obtained using the same chemistry butstarting with the compound:

4,4-(dimethyl-1,1-dioxido-1,2,5-thiadiazolidine-2-yl)-triphenylphosphonium is prepared according to J. Org. Chem. 1994, 59, 2289.

The following methodology applies where Z is F and X is phenyl, C₂-C₈alkyl, C₂-C₈ alkenyl, C₃-C₈ cycloalkyl or C₄-C₈ cycloalkylalkyl.

The “syn” chain fluorinated propanamines may be prepared using themethod outlined below. Although X is shown as optionally substitutedphenyl in the reaction schemes below, the same methodology could beapplied for other identities of X (except thienyl).

The “anti” chain fluorinated propanamines may be prepared using themethod outlined below. Although X is shown as optionally substitutedphenyl in the reaction schemes below, the same methodology could beapplied for other identities of X (except thienyl).

When X is thienyl, the hydroxylated propanamines may be prepared usingthe methodology outlined below.

The synthesis of A is described in the reference S. Kobayashi, I.Hachiya, M. Yasuda; Tetrahedron Letters, 1996, 37(31), 5569-5572. Themixture of stereoisomers obtained by this route is firstly separated byachiral chromatography to give a mixture of chiral diasteroisomers, thenby chiral chromatography to separate the mixture of chiraldiasteroisomeric isomers into individual chiral final products.

When X is thienyl, the fluorinated propanamines may be prepared usingthe methodology outlined below.

The starting material is synthesised as shown in the previous scheme.The mixture of stereoisomers obtained by this route is firstly separatedby achiral chromatography to give a mixture of chiral diasteroisomers,then by chiral chromatography to separate the mixture of chiraldiasteroisomeric isomers into individual chiral final products.

Use of Y—SH in place of Y—OH in the above methodologies where Z is OH orF provides compounds wherein A is S. Note however that for convertinghydroxy to aryl sulfide it is preferred to react the propanol specieswith Y—SH, (cyanomethyl)trimethylphosphonium iodide (Tetrahedron, 2001,57, 5451-5454) and diisopropylamine in propionitrile.

Compounds of formula I where R₁=methyl and R₂=H may be prepared by solidphase synthesis by the route shown below.

The sequence is preferably performed on a macroporous polystyrene resin,e.g. ArgoPore™. Thus ArgoPore-Cl is converted with methylamine inmethanol to a secondary amine bound to the resin. A Mannich typereaction is then performed on the resin bound amine with aqueousformaldehyde, hydrochloric acid a substituted acetophenone andisopropanol. The resultant aminoketone is then reduced with sodiumborohydride in ethanol/triethyleneglycol dimethyl ether to give theamino alcohol. This is then subjected to a Mitsunobu reaction usingdi-t-butylazodicarboxylate, triphenyl phosphine and a heteroarylalcohol/thiol (Y-AH) to give a resin bound heteroaryl aminothioether.Removal of the aminoether from the resin is effected with 1-chloroethylchloroformate and Hunigs base in THF. Finally resolution of theenantiomers is achieved using chiral chromatography.

The following Examples further illustrate the compounds of the presentinvention and methods for their synthesis.

In the following section, there is described the synthesis of precursorsand common intermediates for the compounds of the present invention.

(S)-(−)-3-Iodo-1-Phenyl-1-proyanol

To a solution of (S)-(−)-3-chloro-1-phenyl-1-propanol (5 g, 29.3 mmol)in acetone (50 mL) was added sodium iodide (4.83 g, 32.2 mmol). Theresulting solution was heated at reflux for 16 h. The solution wascooled, filtered and concentrated in vacuo. The residue was purified byflash chromatography eluting silica gel with hexane: ethyl acetate[100:0 to 3:1] to yield the iodo compound (7.44 g, 97%); δ_(H) (300 I,CDCl₃) 7.36 (5H, m, Ar), 4.83 (1H, m, O—CH), 3.34-3.15 (2H, m, CH₂),2.28-2.15 (2H, m, CH₂).

(R)-(+)-3-Iodo-1-phenyl-1-propanol

To a solution of (R)-(+)-3-chloro-1-phenyl-1-propanol (5 g, 29.3 mmol)in acetone (50 mL) was added sodium iodide (4.83 g, 32.2 mmol). Theresulting solution was heated at reflux for 16 h. The solution wascooled, filtered and concentrated in vacuo. The residue was purified byflash chromatography eluting silica gel with hexane: ethyl acetate[100:0 to 3:1] to yield the title compound as a white solid (7.51 g,98%); δ_(H) (300 M1, CDCl₃) 7.36 (5H, m, Ar), 4.83 (1H, m, O—CH),3.34-3.15 (2H, m, CH₂), 2.28-2.15 (2H, m, CH₂).

(1R)-3-Chloro-1-(2-thienyl)-1-propanol a)3-Chloro-1-(2-thienyl)-1-propanone

Chloropropionyl chloride (12 mL, 130 mmol) in dry dichloromethane (50mL) was added dropwise at −5° C. to a stirred suspension of aluminiumchloride (18.8 g, 141 mmol) in dry dichloromethane (100 mL). Theresulting suspension was allowed to stir at −5° C. for 10 mins before asolution of thiophene (10 g, 118 mmol) in dry dichloromethane (50 mL)was added dropwise. The resulting orange solution was stirred at −5° C.for 1 hr before being carefully dropped onto crushed ice (200 g). Theorganic phase was separated and dried (MgSO₄), the solvent was thenpassed through a pad of celite/charcoal to remove any colour. Removal ofthe solvent in vacuo resulted in the title compound as a colourless oil(20 g, 100%); δ_(H) (300 MHz, CDCl₃) 7.75 (1H, d, Ar), 7.68 (1H, d, Ar),7.15 (1H, m, Ar), 3.90 (2H, t, J=7 Hz, CH₂), 3.38 (2H, t, J=7 Hz, CH₂).

b) (1R)-3-Chloro-1-(2-thienyl)-1-propanol

Borane dimethylsulfide complex (2.75 mL, 28.6 mmol) was added at roomtemperature to a stirred solution of (S)-2-methyl-CBS-oxazaborolidine(2.87 mL, 1M) in dry TXF (50 mL). The resulting solution was stirred atroom temperature to 10 mins before a solution of3-chloro-1-(2-thienyl)-1-propanone (2.5 g, 14.3 mmol) in dry THF (100mL) was added dropwise over 1 hr. After complete addition the resultingsolution was stirred at room temperature for a further 1 hr before thesolvent was removed in vacuo. The residue was taken up in ether (200 mL)and washed with NH₄Cl (sat, 100 mL). The organic phase was dried (MgSO₄)and concentrated in vacuo. The residue was purified by flashchromatography eluting silica gel with hexane:ether [7:3] to yield acolourless oil (2.1 g, 84%); Optical purity determined by capillaryelectrophoresis to be 83% ee; δ_(H) (300 Mz, CDCl₃) 7.25 (1H, d, Ar),7.08-6.9 (2H, m, Ar), 5.28-5.20 (1H, m, CHO), 3.80-3.52 (2H, m, CH₂),2.35-2.12 (2H, m, CH₂).

3-[Benzyl(methyl)amino]-1-phenyl-1-propanol

A solution of 3-chloro-1-phenylpropan-1-ol (2 g, 11.7 mmol),N-methylbenzylamine (2.12 g, 17.5 mmol), potassium iodide (2.6 g, 22mmol), and potassium carbonate (3.2 g, 23.4 mmol) in dimethylformamide(120 mL) was stirred at 90° C. in a reacti-vial for 16 h. After thistime the reaction was allowed to cool to room temperature. The reactionmixture was purified by an SCX-2 column eluting with Methanol followedby ammonia:methanol solution (7 N). The organics were then evaporatedand the compound taken directly onto the next step without any furtherpurification. (M⁺H+1 [256]); δ_(H) (300 MHz, CDCl₃) 7.2-7.4 (10H, m,Ar), 4.9 (1H, t, CH—OH), 3.55 (1H, d, CH ₂-Ph), 3.45 (1H, d, CH ₂—PH),2.8-3 (1H, m, CH₂), 2.55-2.65 (1H, m, CH₂), 2.25 (3H, s, CH₃), 1.89-1.9(2H, m, CH₂), 1.6 (1H, brs, OH).

3-(Benzyl-methyl-amino)-N-methoxy-N-methyl-propionamide

Add potassium carbonate (63.50 g, 459 mmol) to a stirred solution ofN-benzylmethylamine (14.8 mL, 115 mmol),3-bromo-N-methoxy-N-methyl-propionamide (22.47 g, 115 mmol, preparedaccording to Jacobi, P. A.; Blum, C. A.; DeSimone, R. W.; Udodong, U. E.S. J. Am. Chem. Soc. 1991, 113, 5384-5392), and anhydrous acetonitrile(460 mL). Heat the reaction to reflux under nitrogen for 3 hours. Coolthe reaction to room temperature and filter the reaction throughCelite®. Wash the Celite® with ethyl acetate and concentrate on a rotaryevaporator to give the crude product. Purify the crude product by flashchromatography on silica gel eluting with 0.5% concentrated ammoniumhydroxide/5% ethanol/chloroform to yield 22.31 g (82%) of3-(benzyl-methyl-amino)-N-methoxy-N-methyl-propionamide: mass spectrum(ion spray) m/z=237.1(M+1); ¹H NMR (CDCl₃) δ 7.31-7.21 (m, 5H), 3.65 (s,3H), 3.53 (s, 2H), 3.17 (s, 3H), 2.80-2.76 (m, 2H), 2.67-2.63 (m, 2H),2.23 (s, 3H).

1-(Benzyl-methyl-amino)-heptan-3-one

Add butyllithium (12.3 ml (1.6 M solution in hexane), 19.6 mmol) to astirred solution of3-(benzyl-methyl-amino)-N-methoxy-N-methyl-propionamide and anhydroustetrahydrofuran (70 ml) at −40° C. under N₂. Stir for 1 hr at −40° C.Quench the reaction with saturated ammonium chloride (25 ml), allow thereaction to reach room temperature and add saturated sodium bicarbonate.Extract with ethyl acetate, wash with brine and dry over sodium sulfate.Filter off and concentrate to give the crude product. Purify thecompound by flash chromatography, eluting with 2% ethanol/0.2% ammoniumhydroxide/chloroform to yield 2.41 g (81%) of1-(benzyl-methyl-amino)-heptan-3-one: mass spectrum (ion spray) m/z=234(M+1); ¹H NMR (CDCl₃) δ 7.31-7.24 (m, 5H), 3.5 (s, 2H), 2.74-2.7 (m,2H), 2.64-2.60 (m, 2H), 2.41 (t, 2H ), 2.19 (s, 3), 1.59-1.51 (m, 2H),1.35-1.28 (m, 2H), 0.91 (t, 3H).

1-(Benzyl-methyl-amino)-hexan-3-one

Using a method similar to that for 1-Benzyl-methyl-amino)-heptan-3-one,propylmagnesium chloride (2 M solution in diethyl ether) affords thetitle compound: mass spectrum (ion spray) m/z=220 (M+1): 1H NMR (CDCl₃)δ 7.35-7.24 (m, 5H), 3.51 (s, 2H), 2.74-2.69 (m, 2H), 2.66-2.61 (m, 2H),2.39 (t, 2H), 2.20 (s, 3H), 1.67-1.57 (m, 2H), 0.92(t, 3H),

(4-Cyclohexyl-3-oxo-butyl)-methyl-carbamic acid tert-butyl ester

Add dropwise bromomethylcyclohexane (16.96 mL, 0.121 mol) to a stirredwarm solution of magnesium (granulae, 3.02 g, 0.124 mol), a crystal ofiodine and tetrahydrofuran (130 mL). Heat the mixture to reflux for onehour. Add the Grignard reagent (30 mL) to a stirred mixture of[2-(methoxy-methyl-carbamoyl)-ethyl]-methyl-carbamic acid tert-butylester (3.0 g, 12.0 mmol, prepared according to Blaney, P.; Grigg, R.;Rankovic, Z.; Thornton-Pett, M.; Xu, J. Tetrahedron 2002, 1719-1737) andtetrahydrofuran (120 mL) kept at 0° C. under N₂. Stir the mixture forone h at 0° C. and for 2 h at room temperature. Add more of the Grignardreagent (40 mL) and stir for another hour at room temperatur. Addsaturated aqueous ammonium chloride and separated the layers. Extractthe water layer with diethyl ether (x3). Dry the combined organiclayers, filter and concentrate. Purify the crude residue by flash columnchromatography, eluting with ethyl acetate/hexane (1:9) to yield 1.0 gof the title compound. ¹H NMR (CDCl₃) δ 3.46-3.40 (m, 2I1), 2.85 (s,3H), 2.68-2.60 (m, 2H), 2.29 (d, 2H), 1.87-1.60 (m, 6H), 1.46 (s, 9H),1.33-1.07 (m, 3H), 0.99-0.86 (m, 2H).

1-(Benzyl-methyl-amino)-heptan-3-ol

Add sodium borohydride (1.29 g, 34.1 mmol) to a stirred solution of1-(benzyl-methyl-amino)-heptan-3-one (2.41 g, 10 mmol) and methanol(45ml) at 0° C. under N₂. Stir the reaction for 1 hr at 0° C. Quench thereaction with water at 0° C. and concentrate under reduced pressure.Dissolve the residue in ethyl acetate, wash with brine and dry oversodium sulfate. Filter off and concentrate to give the crude compound.Purify the compound by flash chromatography, eluting with 5%ethanol/0.5% ammonium hydroxide/chloroform to yield 2.22 g (91%) of1-(benzyl-methyl-amino)-heptan-3-ol: mass spectrum (ion spray) m/z=236(M+1); ¹H NMR (CDCl₃) δ 7.34-7.23 (m, 5H), 3.76-3.72 (m, 1H), 3.53 (dd,2H), 2.80-2.73 (m, 1H), 2.59-2.53 (m, 1H), 2.21 (s, 1H), 1.68-1.62 (m,1H), 1.57-1.29 (m, 7H), 0.91 (t, 3H).

1-(Benzyl-methyl-amino)-hexan-3-ol

Using a method similar to that for 1-(Benzyl-methyl-amino)-heptan-3-ol,1-(benzyl-methyl-amino)-hexan-3-one affords the title compound: massspectrum (ion spray) m/z 222 (M+1); ¹H NMR (CDCl₃) δ 7.34-7.24 (m, 5H),3.79-3.73 (m, 1H), 3.55 (dd, 2H), 2.81-2.74 (m, 1H), 2.59-2.55 (m, 1H),2.22 (s, 3H), 1.72-1.62 (m, 1H), 1.56-1.31 (m, 5H), 0.93 (t, 3H).

(4-Cyclohexyl-3-hydroxy-butyl)-methyl-carbamic acid tert-butyl ester

Using a method similar to that for 1-(Benzyl-methyl-amino)-heptan-3-ol,(4-cyclohexyl-3-oxo-butyl)-methyl-carbamic acid tert-butyl ester affordsthe title compound: ¹H NMR (CDCl₃) δ 3.90-3.80 (m, 1H), 3.62-3.52 (m,1H), 2.88-2.96 (m, 1H), 2.83 (3H), 1.80-1.60 (m, 6H), 1.56-1.32 (m, 3H),1.47 (s, 9H), 1.31-1.08 (m, 4H), 0.98-0.77 (m,2H),

1-(Benzyl-methyl-amino)-5-methyl-hexan-3-ol

Add N-benzylmethylamine (1.50 mL, 11.6 mmol) to a stirred solution of1,8-diazabicyclo[5.4.0]undec-7-ene (0.0175 mL, 0.117 mmol) and anhydroustetrahydrofuran (10 mL). Cool the solution to −15° C. under nitrogen.Add acrolein (0.78 mL, 11.7 mmol) slowly and stir for 30 minutes at −15°C. Cool the reaction to −78° C. Add isobutylmagnesium chloride (11.0 mL,2.0 M solution in diethyl ether, 22.0 mmol) and stir for 1 hour at −78°C. Quench the reaction with water at −78° C and then pour the reactioninto 100 mL of IN sodium hydroxide/saturated sodium bicarbonate (1:1).Extract with ethyl acetate (3×100 mL), wash the ethyl acetate with brine(100 mL), and dry the ethyl acetate over sodium sulfate. Filter off thesodium sulfate and concentrate on a rotary evaporator to give the crudeproduct. Purify the crude product by flash chromatography on silica geleluting with 0.3% concentrated ammonium hydroxide/3% ethanol/chloroformto yield 1.0010 g (37%) of 1-(benzyl-methyl-amino)-5-methyl-hexan-3-ol:mass spectrum (ion spray) m/z=236.2(M+1); ¹H NMR (CDC₃) δ 7.34-7.23 (m,5H), 6.08 (br s, 1H), 3.86-3.80 (m, 1H), 3.62 (d, 1H), 3.43 (d, 1H),2.79-2.73 (m, 1H), 2.58-2.53 (m, 1H), 2.21 (s, 3H), 1.83-1.40 (m, 4H),1.16-1.09 (m, 1H), 0.91-0.89 (m, 6H).

1-(Benzyl-methyl-amino)-4-methyl-pentan-3-ol

Using a method similar to that for1-(Benzyl-methyl-amino)-5-methyl-hexan-3-ol, isopropylmagnesium chlorideaffords the title compound: mass spectrum (ion spray) m/z=222.1(M+1); ¹HNMR (CDCl₃) δ 7.34-7.23 (m, 5H), 6.21 (br s, 1H), 3.63 (d, 1H),3.51-3.47 (m, 1H), 3.42 (d, 1H), 2.81-2.74 (m, 1H), 2.59-2.54 (m, 1H),2.19 (s, 3H), 1.72-1.47 (m, 3H), 0.95 (d, 3H), 0.89 (d, 3H).

Isoquinolin-4-ol

The title compound was prepared as described in Tetrahedron, 1963, 19,827-832.

Isoquinolin-6-ol a) 6-Methoxy-isoquinoline

The title compound was prepared as described in Synth. Commun., 1999,29, 1617-1625.

b) Isoquinolin-6-ol

Heat a mixture of 6-methoxy-isoquinoline (2.1 g, 13.2 mmol) and pyridinehydrochloride (30 g) in a heavy walled screw cap sealed tube at 160° C.overnight. Cool to room temperature, add water and concentrated ammoniumhydroxide to bring the pH of the mixture to 10-11, extract with ethylacetate (4 times), wash the combined organic extracts with water (4times), and concentrate under reduced pressure. Purification by mediumpressure liquid chromatography eluting with 0-3% of 2N NH₃/MeOH indichloromethane afford the title compound (520 mg, 27%): δ_(H) (DMSO-d6,400 MHz): 7.09 (s, 1H), 7.19 (dd, 1H, J=9, 2 Hz), 7.56 (d, 1H, J=6Hz),7.94 (d, 1H, J=9 Hz), 8.29 (d, 1H, J=6 Hz), 9.05 (s, 1H), 10.36 (s,1H).

[1.7]Naphthyridin-5-ol

The title compound was prepared as described in Liebigs Annalen DerChemie, 1979, 443-445.

5-Hydroxyisoquinoline

The title compound is commercially available and was purchased from theAldrich Chemical Company.

5-Quinolinol

The title compound is commercially available and was purchased from theAldrich Chemical Company.

Benzo[d]isothiazol-4-ol a) 4-Methoxy-benzo[d]isothiazole

To a solution of 2-fluoro-6-methoxybenzaldehyde (2.0 g, 13.0 mmol) in2-methoxyethanol (10 mL) in a sealed tube was added sulfur (416 mg, 13.0mmol) and aqueous ammonium hydroxide (10 mL). The solution was heated to160 degC. for 18 h and was then cooled to rt. The reaction waspartitioned between dichloromethane and water. The organic layer wasseparated and the aqueous layer was extracted with 2×50 mLdichloromethane. The combined organic phases were dried (MgSO₄) andconcentrated in vacuo. The residue was purified by flash chromatographyeluting silica gel with EtOAc:hexane [0:100 to 4:6] to yield the titlecompound as an oil (1.51 g, 70%); Mass spectrum (ion spray): m/z=165.9(m+1).

b) Benzo[d]isothiazol-4-ol

To a sealed tube was added 4-methoxy-benzo[d]isothiazole (760 mg, 4.60mmol) and pyridine hydrochloride (5.5 g, 48 mmol). The reaction washeated to 150° C. for 18 h and was then cooled to rt. The mixture waspartitioned between dichloromethane and water. The organic phase wasseparated and the aqueous layer was extracted with 2×30 mLdichloromethane. The combined organic phases were dried (MgSO₄) andconcentrated in vacuo. The residue was purified by flash chromatographyeluting silica gel with EtOAc:hexane [0:100 to 3:7] to yield the titlecompound as a solid (223 mg, 32%); Mass spectrum (ion spray): m/z=151.9(m+1).

7-methyl-benzo[d]isothiazol-4-ol a) 7-Bromo-4methoxy-benzo[d]isothiazole

To a solution of 4-methoxy-benzo[d]isothiazole (prepared as describedabove) (1.0 g, 6.05 mmol) in carbon tetrachloride (20 mL) at 0° C. wasadded bromine (310 μL, 6.05 mmol) in carbon tetrachloride (10 mL). Thereaction was allowed to stir at 0° C. for 3 h and was then warmed to rt.Saturated aqueous NaHCO₃ and dichloromethane were added and the organicphase was separated. The aqueous phase was extracted with 2×20 mLdichloromethane. The combined organic phases were dried MgSO₄) andconcentrated in vacuo. The residue was purified by flash chromatographyeluting silica gel with FtOAc:hexane [0:100 to 1:20] to yield the titlecompound (980 mg, 66%): δ_(H) (300 MHz, CDCl₃): 9.09 (1H, s), 7.52 (1H,d, J=8.1 Hz), 6.67 (1H, d, J=8.4 Hz), 4.00 (3H, s).

b) 7-methyl-benzo[d]isothiazol4-ol

A solution of 7-4-methoxy-benzo[d]isothiazole (460 mg, 1.88 mmol), K₂CO₃(780 mg, 5.64 mmol), and Pd(PPh₃)₄ (217 mg, 0.188 mmol) in 1,4-dioxane(5 mL) was added trimethylboroxine (290 μL, 2.07 mmol) and the solutionwas heated to 110° C. for 18 h. The reaction was cooled to rt anddiluted with water and dichloromethane. The organic phase was separatedand the aqueous phase was extracted with 2×30 mL dichloromethane. Thecombined organic phases were dried (MgSO₄) and concentrated in vacuo.The residue was purified by flash chromatography eluting silica gel withEtOAc:hexane [0:100 to 1:10] to yield4-methoxy-7-methyl-benzo[d]isothiazole (88 mg, 26%). A method similar tothat described for the preparation of benzo[d]isothiazol4-ol (above)using 4-methoxy-7-methyl-benzo[d]isothiazole (88 mg, 0.491 mmol) andpyridine hydrochloride (567 mg, 5 mol) gave the title compound (30 mg,37%): δ_(H) (300 MHz, CDCl₃): 8.99 (1H, s), 7.15 (1H, d, J=7.5 Hz), 6.70(1H, d, J=7.5 Hz), 2.45 (3H, s).

Benzo[d]isothiazol-7-ol a) 2-Fluoro-3,N-dimethoxy-N-methyl-benzamide

To a solution of 2-fluoro-3-methoxy-benzoic acid (5.0 g, 29.4 mmol) andPyBOP (13.7 g, 29.4 mmol) in 7:1 CH₂Cl₂:THP was added triethylamine(4.10 mL, 29.4 mmol) over a 10 min period. N,O-Dimethylhydroxylaminehydrochloride (2.87 g, 29.4 mL) was then added and the reaction wasallowed to stir at rt for 3 h. The reaction was then partitioned betweendichloromethane and water. The organic phase was separated and theaqueous phase was extracted with 2×100 mL dichloromethane. The combinedorganic phases were dried (MgSO₄) and concentrated in vacuo. The residuewas taken up in ethyl acetate and was washed successively with 1N HCl,saturated aqueous NaHCO₃, and brine. The organic phase was again dried(MgSO₄) and concentrated in vacuo to yield the title compound (2.30 g,37%).

b) 2-Fluoro-3-methoxy-benzaldehyde

To a solution of 2-fluoro-3,N-dimethoxy-N-methyl-benzamide (2.30 g, 10.8mmol) in THF (20 mL) at −78° C. was added 1M DEBAL-H in toluene.(12 mL,12 mmol). The reaction stirred at −78° C. for 3 h and then the remaining1M DIDAL-H in toluene (4.2 mL, 4.2 mmol) was added to the reaction. Thereaction was allowed to stir at −78° C. for 30 min and was then warmedto rt. The reaction was quenched slowly with saturated aqueous NH₄Cl.The organic phase was separated and the aqueous phase was extracted with2×50 mL ethyl acetate. The combined organic phases were washedsuccessively with 1N HCl and brine. The organic phase was dried (MgSO₄)and concentrated in vacuo. The residue was purified by flashchromatography eluting silica gel with EtOAc:hexane [0:100 to 1:1) toyield the title compound (1.41 g, 85%): δ_(H) (300 MHz, CDCl₃): 10.38(1H, s), 7.43-7.40 (1H, m), 7.24-7.15 (2H, m), 3.95 (3H, s).

c) 7-methoxy-benzo[d]isothiazole

A method similar to 4-methoxy-benzo[d]isothiazole using2-fluoro-3-methoxy-benzaldehyde (410 mg, 2.66 mmol), sulfur (85 mg, 2.66mmol), NH₄OH (5 mL), and 2-methoxyethanol (5 mL) gave the title compound(60 mg, 14%); Mass spectrum (ion-spray): m/z=165.8 (m+1).

d) Benzo[d]isothiazol-7-ol

A method similar to that used in the preparation ofbenzo[d]isothiazol-4-ol using 7-methoxy-benzo[d]isothiazole (60 mg,0.363 mmol) and pyridine hydrochloride (500 mg, 4.33 mmol) gave thetitle compound (26 mg, 47%); Mass spectrum (ion-spray): m/z=151.9 (m+1).

4-Hydroxy-benzothiazole a) 4-Methoxy-benzothiazole

2-Amino-4-methoxy-benzothiazole (1.00 g, 5.54 mmol) was added to astirred solution of polyphosphoric acid (85%, 40 ml) at 60° C. Theresulting mixture was stirred at 60° C. until all the benzothiazole haddissolved. The resulting solution was then cooled to −10° C. and asolution of sodium nitrite (2.3 g, 33.3 mmol) in water (5 ml) was addedso as to keep the internal temperature below −4° C. After completeaddition the resulting solution was added to a solution ofhypophosphoric acid (50%, 15 ml) at 0° C. After the evolution of gas hadceased the mixture was diluted with water and basified with NaHCO₃(sat). The aqueous solution was extracted with CHCl₃ (3×200 ml) with thecombined organic extracts dried (MgSO₄) and the solvent removed invacuo. The resulting solid was recrystallised from EtOH:H₂O to give anorange solid (300 mg).

The liquor was concentrated and purified by flash chromatography elutingsilica gel with hexane:EtOAc [4: 1] to hexane:EtOAc [1: 1] to give afurther 210 mg of product. R_(f)=0.38 in hexane:ether [1:1]; δ_(H) (300MHz, CDCl₃) 8.91 (1H, s, CH), 7.53 (1H, d, Ar), 7.39 (1H, t, Ar), 6.93(1H, d, Ar), 4.07 (3H, s, OCH₃).

b) 4-Hydroxy-benzothiazole

Boron tribromide (3.09 ml, 1M solution in DCM, 3.09 mmol) was addeddropwise at 0° C. to a stirred solution of 4-methoxy-benzothiazole (510mg, 3.09 mmol) in dry DCM (30ml). The resulting solution was warmed to40° C. and allowed to stir overnight. The resulting solution wasconcentrated in vacuo and diluted with water and HCl (2N). The aqueousphase was neutralised to pH ˜7 with NaHCO₃ and the solution extractedwith EtOAc (3×100 ml) and the combined organic extracts dried (MgSO₄)and the solvent removed in vacuo. The resulting oil was purified byflash chromatography eluting silica gel with hexane:EtOAc [4:1] tohexane:EtOAc [7:3] to give the title compound as a tan solid (730mg,80%); δ_(H) (300 MHz, CDCl₃) 7.59 (1H, s, CH), 7.46 (1H, dd, Ar), 7.36(1H, t, Ar), 7.02 (1H, dd, Ar).

Thieno[3,2-c]pyridin-7-ol

The title compound was prepared as described in Patent GB 2010249A.

Thieno[2,3-c]pyridin-4-ol

The title compound was prepared as described in Patent GB 2010249A.

4-Fluoro-2,3-dihydrobenz[b]thiophen-7-ol a)5-(2-Fluoro-5-methoxybenzylidene)-2-thioxo-1,3-thiazolidin4-one

To a suspension of 2-fluoro-5-methoxybenzaldehyde (5.00 g, 32.46 mmol)and rhodanine (4.31 g, 32.46 mmol) in dry toluene (1000 mL) was addedammonium acetate (50 mg) and acetic acid (2 mL). The resultingsuspension was allowed to stir at 120° C. for 12 h under Dean—Starkapparatus before being allowed to cool and filtered. Resultant solid waswashed with hexane and allowed to dry in vacuo to give an orangecrystalline solid (8.00 g, 91%); δ_(H) (300 MHz, CDCl₃) 7.50 (1H, s,CH═C); 7.31 (1H, t, Ar), 7.20-7.11 (1H, m Ar), 6.95-6.89 (1H, m, Ar),3.80 (3H, s, OCH₃).

b) (2Z)-3-(2-Fluoro-5-methoxyphenyl)-2-mercapto-2-propenoic acid

5-(2-Fluoro-5-methoxybenzylidene)-2-thioxo-1,3-thiazolidin4-one (8.00g,9.7 mmol) was added in one portion to 25% w/v sodium hydroxide solution(40 mL). This was allowed stir at reflux for 1 h. After this time thereaction was allowed to cool to room temperature and poured onto water(50 mL). This was washed with dichloromethane (50 mL), and the aqueouslayer acidified to pH 2 with aqueous hydrochloric acid (2 N, 50 mL) togive a white suspension. Product was extracted with ether (2×60 mL),dried (MgSO₄) and solvent removed in vacuo to give a white solid (6.71g, 100%); OH (300 MHz, CD₃OD) 7.85 (1H, s, Ar), 7.46-7.35 (1H, m, Ar),7.11 (1H, t, Ar), 7.01-6.75 (2H, m, CH=, and SH), 3.80 (3H, s, OCH₃).

c) 4-Fluoro-7-methoxy-1-benzothiophene-2-carboxylic acid

(2Z)-3-(2-Fluoro-5-methoxyphenyl)-2-mercapto-2-propenoic acid (1.00 g,4.38 mmol) was added in one portion to a solution of iodine (1.66 g,6.56 mmol) in dimethoxyethane (10 mL). This was heated in the microwavewith 300 W at 160° C. for 10 mins. After this time the reaction wasallowed to cool to room temperature and poured onto saturated sodiummetabisulphite (200 mL) and ether (400 mL). Ether layer was separatedand product extracted with aqueous sodium hydroxide (2 N, 2×100 mL).This was then acidified to pH 2 with aqueous hydrochloric acid (2 N, 250mL), and product extracted with ether (2×150 mL). The combined organicextracts were dried (MgSO₄) and concentrated in vacuo to give a whitesolid (580 mg, 30%); δ_(H) (300 MHz, CD₃OD) 8.00 (1H, s, Ar), 7.30-7.19(1H, m, Ar), 7.10-7.00 (1H, m, Ar), 3.95.(3H, s, OCH₃).

d) -Fluoro-7-methoxy-1-benzothiophene

4-Fluoro-7-methoxy-1-benzothiophene-2-carboxylic acid (2.00 g, 8.84mmol) was added in one portion to DBU (8 mL) and dimethyl acetamide (10mL). This was heated in the microwave with 300 W at 200° C. for 1 h. Thereaction mixture was allowed to cool and poured onto water (100 mL).Product was extracted with hexane (2×100 mL), washed with aqueoushydrochloric acid (2 N, 50 mL), aqueous sodium hydroxide (2 N, 50 mL),and the combined organic extracts were dried (MgSO₄) and concentrated invacuo. The residue was purified by flash chromatography eluting silicagel with hexane:ethyl acetate [96:4] to give an oil (1.12 g, 70%): δ_(H)(300 MHz, CDCl₃) 7.4 (2H, s, Ar), 6.9 (1H, t, Ar), 6.60 (1H, dd, Ar),3.91 (3H, s, OCH₃).

e) 4-Fluoro-7-methoxy-2,3-dihydrobenzo[b]thiophene

To a solution of 4-fluoro-7-methoxy-1-benzothiophene (1.55 g, 8.5 mmol,1 eq) in trifluoroacetic acid (40 ml) was added triethylsilane (3.40 ml,21.25 mmol, 2.5 eq). The mixture was heated to 60° C. for 48 hours, thencooled to room temperature and the solvent removed in vacuo. The crudeproduct was purified by flash chromatography with a gradient of 40-60%chloroform in heptane to give 1.24 g, 80% recovered starting materialand 199 mg, 13% yield of the title compound as a colourless oil: OH (300MHz, CDCl₃) 3.78-6.58 (2H, m, ArH), 3.82 (3H, s, CH₃) and 3.44-3.30 (4H,m, SCH₂CH₂).

f) 4Fluoro-2,3-dihydrobenzo[b]thiophen-7-ol

A BBr3 demethylation of 4-fluoro-7-methoxy-2,3-dihydrobenzo[b]thiophenesimilar to that described for 4hydroxy benzothiazole affords the titlecompound as a brown solid 251 mg: δ_(H) (300 MHz, CDCl₃) 6.57-6.48 (2H,m, ArH), 4.67 (1H, br. s, OH) and 3.43-3.23 (4H, m, SCH₂CH₂).

4-[(3R)-3-Chloro-1-phenyl-propoxy]-isoquinoline

Add 4,4-(dimethyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)-triphenylphosphonium (547 mg, 1.4 mmol, 1.2 equiv. Prepared as described in J.Org. Chem. 1994, 59, 2289.) to a stirred solution of(S)-(−)-3-chloro-1-phenyl-1-propanol (306 mg, 1.17 mmol, 1 equiv.) andisoquinolin-4-ol (206 mg, 1.42 mmol, 1.2 equiv. prepared as described inTetrahedron, 1963, 19, 827-832) in dry toluene (11 mL) and stir at roomtemperature for 18 hr. Add ethyl acetate, water, and brine, separate thelayers, and extract the aqueous layer with ethyl acetate (3 times). Washthe combined organic extracts with brine (2 times), dry over anhydrousmagnesium sulfate, filter, and concentrate under reduced pressure.Purification by medium pressure liquid chromatography eluting with 0-50%ethyl acetate in hexanes affords the title compound as a pale yellow oil(163 mg, 47%): δ_(H) (CDCl₃, 400 MHz): 2.32-2.42 (m, 1H), 2.66-2.71 (m,1H), 3.64-3.72 (m, 1H), 3.82-3.91 (m, 1H), 5.67 (dd, 1H, J=9, 5 Hz),7.25-7.37 (m, 3H), 7.40-7.46 (m, 2H), 7.62 (ddd, 1H, J=7, 7, 2 Hz), 7.73(ddd, 1H, J=7, 7, 1 Hz), 7.91 (d, 1H, J=8 Hz), 7.93 (s, 1H), 8.33 (dd,1H, J=8, 1 Hz), 8.83 (s, 1H).

Similarly prepared were

6-[(3R)-3-Chloro-1-phenyl-propoxy]-isoquinoline

as a pale yellow oil: δ_(H) (CDCl₃, 400 MHz): 2.25-2.35 (m, 1H),2.50-2.60 (m, 1H), 3.60-3.69 (m, 1H), 3.80-3.90 (m, 1H), 5.58 (dd, 1H,J=9, 5 Hz), 6.96 (d, 1H, J=2 Hz), 7.23-7.47 (m, 7H), 7.84 (d, 1H, J=10Hz), 8.36 (br s, 1H), 9.01 (br s, 1H).

5-[(3R)-3-Chloro-1-phenyl-propoxy]-[1,7]naphthyridine

using [1,7]naphthyridin-5-ol (prepared as described in Liebigs AnnalenDer Chemie, 1979, 443-445) affords the title compound as a gummy yellowoil (349 mg, 74%): δ_(H) (CDCl₃, 400 MHz): 2.32-2.43 (m, 1H), 2.60-2.71(m, 1H), 3.60-3.67 (m, 1H), 3.78-3.87 (m, 1H), 5.67 (dd, 1H, J=8, 5 Hz),7.25-7.45 (m, 5H), 7.63 (dd, 1H, J=9, 5 Hz), 8.02 (br s, 1H), 8.65 (dd,1H, J=9, 1 Hz), 9.02 (dd, 1H, J=5, 1 Hz), 9.09 (br s, 1H).

5-[(3R)-3-Chloro-1-phenyl-propoxy]-isoquinoline

using 5-hydroxy isoquinoline (commercially available from the AldrichChemical Company) affords the title compound as a yellow oil (550 mg,74%): δ_(H) (CDCl₃, 400 MHz): 2.31-2.42 (m, 1H), 2.60-2.70 (m, 1H),3.64-3.72 (m, 1H), 3.82-3.91 (m, 1H), 5.63 (dd, 1H, J=8, 5 Hz), 6.89 (d,1H, J=8 Hz), 7.26-7.44 (m, 6H), 7.51 (d, 1H, J=8 Hz), 8.18 (d, 1H, J=6Hz), 8.57(d, 1H, J=6 Hz), 9.21 (br d, 1H).

5-[(3R)-3-Chloro-1-phenyl-propoxy]-quinoline

using 5quinolinol (commercially available from the Aldrich ChemicalCompany) affords the title compound as a colorless foam (93 mg, 40%):δ_(H) (CDCl₃, 400 MHz): 2.24-2.34 (m, 1H), 2.52-2.62 (m, 1H), 3.55-3.63(m, 1H), 3.74-3.82 (m, 1H), 5.54 (dd, 1H, J=8,4 Hz), 6.65 (d, 1H, J=8Hz), 7.18-7.40 (m, 7H), 7.56 (d, 1H, J=8 Hz), 8.63 (ddd, 1H, J=8, 1, 1Hz), 8.84 (dd, 1H, J=5, 2 Hz).

(1R)-4-Fluoro-7-(3-iodo-1-phenyl-propoxy)-2,3-dihydrobenzo[b]thiophene

using (S)-1-iodo-3-phenyl-3-propanol with4fluoro-2,3-dihydrobenzo[b]thiophen-7-ol, to give 243 mg of the titlecompound as a colourless solid: δ_(H) (300 MHz, CDCl₃) 7.32-7.12 (5H, m,3-ArH), 6.46-6.27 (3H, m, ArH), 5.15-5.06 (1H, m, CHO), 3.43-3.11 (6H, mCH₂CH₂HI and SCH₂CH₂), 2.50-2.31 (1H, m, CHHCH₂I) and 2.27-2.09 (1H, m,CHHCH₂I).

4-[(1R)-3-chloro-1-phenylpropyl]oxy-1-benzothiazole

as a colourless oil (200 mg, 100%); R_(f)=0.40 in hexane:ether [1:1]:δ_(H) (300 MHz, CDCl₃) 8.95 (1H, s, Ar), 7.49-6.81 (8H, m, Ar),5.73-5.68 (1H, m, CHO), 3.94-3.91 (1H, m, CH), 3.72-3.67 (1H, m, CH),2.73-2.71 (1H, m, CHH), 2.40-2.30 (1H, m, CHH).

(3R)-3-(1,3-Benzothiazol-4-yloxy)-N-methyl-3-phenyl-N-(phenylmethyl)-propan-1-amine

N-Methyl benzylamine (100 W, 0.79 mmol) was added to a stirredsuspension of 4-[(1R)-3-chloro-1-phenylpropyl]oxy-1-benzothiazole (200mg, 0.658 mmol) and K₂CO₃ (450 mg, 3.29 mmol) and potassium iodide (110mg, 0.658 mmol) in MeCN (20 ml). The resulting suspension was stirred at60° C. for 48 hrs. After this time the reaction was allowed to cool toroom temperature and diluted with water (ca. 50 ml) and extracted withEtOAc (3×50 ml). The combined organic extracts were dried MgSO₄) and thesolvent removed in vacuo. The resulting oil was purified by flashchromatography eluting silica gel with DCM:MeOH [97.5:2.5] to DCM:MeOH[9:1] to give the title compound as a tan oil (180mg, 70%); R_(f)=0.40in DCM:MeOH [9:1]: δ_(H) (300 MHz, CDCl₃) 8.90 (1H, s, Ar), 7.45-6.77(13H, m, Ar), 5.64-5.59 (1H, m, CHO), 3.46 (2H, dd, CH₂), 2.78-2.68 (1H,m, CH), 2.53-2.44 (2H, m, CH₂), 2.21 (3H, s, CH₃), 2.14-2.11 (1H, m,CH).

7-[(1R)-(3-Chloro-1-phenyl-propoxy)]-thien[3,2-b]pyridine

(S)-(−)-3-chloro-1-phenyl-1-propanol (1 g, 5.8 mmol) andthieno[3,2-b]pyridin-7-ol (1.15 g, 7.6 mmol, commercially available fromthe Aldrich Chemical Company) in dry TBF (6 ml) were stirred under aninert atmosphere of nitrogen. PPh₃ (1.99 g, 7.6 mmol) followed by DEAD(1 mL, 7.6 mmol) were added and the resulting solution was allowed tostir for a further 72 h while heating at 40° C. before the solvent wasremoved in vacuo. The residue was purified by flash chromatography,eluting silica gel with hexane: ethyl acetate [100:0 to 1:3] to yieldthe title compound (1.38 g, 78%); mass spectrum (ion spray): m/z=304.05(m+1).

Prepared similarly was

7-[(1S)-(3-Chloro-1-phenyl-propoxy)]-thieno[3,2-b]pyridine

using (R)-(+)-3-chloro-1-phenyl-1-propanol, thieno[3,2-b]pyridin-7-ol(commercially available from the Aldrich Chemical Company), PBu₃, andADPP gave the title compound (0.71 g, 54%); Mass spectrum (ion spray):m/z=304.06 (m+1).

7-[(1R)-(3-Iodo-1-phenyl-propoxy)]-thieno[3,2-b]pyridine

To a solution of7-[(1R)-(3-Chloro-1-phenyl-propoxy)]-thieno[3,2-b]pyridine (703 mg, 2.3mmol) in 15 mL of acetone was added NaI (3.5 g, 23 mmol). The resultingsolution was allowed to stir at 55° C. for 18 h before removing theacetone in vacuo. The residue was taken up in CH₂Cl₂ and water. Thelayers were separated and the aqueous phase was further extracted 2times with CH₂Cl₂. The combined organic phase was dried (MgSO₄) andconcentrated in vacuo. The residue was purified by flash chromatographyeluting silica gel with hexane: ethyl acetate [100:0 to 1: 1] to yieldthe title compound (0.79 g, 87%); mass spectrum (ion spray): m/z=395.98(m+1).

Prepared similarly was

7-[(1S)-(3-Iodo-1-phenyl-propoxy)]-thieno[3,2-b]pyridine

using 7-[(1S)-(3-chloro-1-phenyl-propoxy)]-thieno[3,2-b]pyridine gavethe title compound (0.22 g, 71%); Mass spectrum (ion spray): m/z=395.99(m+1).

4-[(3S)-3-Chloro-1-phenyl-propoxy]-isoquinoline

Add 4,4-(dimethyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)-triphenylphosphonium (790 mg, 2.0 mmol, 1.3 equiv.) to a stirred solution of(R)-(+)-3-chloro-1-phenyl-1-propanol (404 mg, 1.54 mmol, 1 equiv.) andisoquinolinfol (293 mg, 2.0 mmol, 1.3 equiv., prepared as described inTetrahedron, 1963, 19, 827-832) in dry toluene (15 mL) and stir at roomtemperature for 18 hr. Add ethyl acetate, water, and brine, separate thelayers, and extract the aqueous layer with ethyl acetate (3 times). Washthe combined organic extracts with brine (2 times), dry over anhydrousmagnesium sulfate, filter, and concentrate under reduced pressure.Purification by medium pressure liquid chromatography eluting with 0-20%ethyl acetate in hexanes affords the title compound as a pale yellow oil(229 mg, 50%): δ_(H) (CDCl₃, 400 MHz): 2.32-2.42 (m, 1H), 2.66-2.71 (m,1H), 3.64-3.72 (m, 1H), 3.82-3.91 (m, 1H), 5.67 (dd, 1H, J=9, 5 Hz),7.25-7.37 (m, 3H), 7.40-7.46 (m, 2H), 7.62 (ddd, 1H, J=7, 7, 2 Hz), 7.73(ddd, 1H, J=7, 7, 1 Hz), 7.91 (d, 1H, J=8 Hz), 7.93 (s, 1H), 8.33 (dd,1H, J=8, 1 Hz), 8.83 (s, 1H).

Similarly prepared were

6-[(3S)-3-Chloro-1-phenyl-propoxy]-isoquinoline

as a pale yellow oil: δ_(H) (CDCl₃, 400 MHz): 2.25-2.35 (m, 1H),2.50-2.60 (m, 1H), 3.60-3.69 (m, 1H), 3.80-3.90 (m, 1H), 5.58 (dd, 1H,J=9, 5 Hz), 6.96 (d, 1H, J=2 Hz), 7.23-7.47 (m, 7H), 7.84 (d, 1H, J=10Hz), 8.36 (br s, 1H), 9.01 (br s, 1H).

5-[(3S)-3-Chloro-1-phenyl-propoxy]-isoquinoline

as a colorless oil (320 mg, 56%): δ_(H) (CDCl₃, 400 MHz): 2.31-2.42 (m,1H), 2.60-2.70 (m, 1H), 3.64-3.72 (m, 1H), 3.82-3.91 (m, 1H), 5.63 (dd,1H, J=8, 5 Hz), 6.89 (d, 1H, J=8 Hz), 7.26-7.44 (m, 6H), 7.51 (d, 1H,J=8 Hz), 8.18 (d, 1H, J=6 Hz), 8.57(d, 1H, J=6 Hz), 9.21 (br d, 1H).

(1S)-4-Fluoro-7-(3-iodo-1-phenyl-propoxy)-2,3-dihydrobenzo[b]thiophene

using (R)-1-iodo-3-phenyl-3-propanol with4-fluoro-2,3-dihydrobenzo[b]thiophen-7-ol, to give 242 mg of the titlecompound as a colorless solid: δ_(H) (300 MHz, CDCl₃) 7.32-7.12 (5H, m,3-ArH), 6.46-6.27 (3H, m, ArH), 5.15-5.06 (1H, m, CHO), 3.43-3.11 (6H,m, CH₂CH₂HI and SCH₂CH₂), 2.50-2.31 (1H, m, CHHCH₂I) and 2.27-2.09 (1H,m, CHHCH₂I).

5-[(3S)-3-Iodo-1-phenyl-propoxy]-quinoline

Add ADDP (434 mg, 1.72 mmol, 1.5 equiv.) to a stirred solution of of(R)-(+)-3-iodo-1-phenyl-1-propanol (404 mg, 1.54 mmol, 1 equiv.),tri-n-butyl phosphine (428 μl, 1.72 mmol, 1.5 equiv.), and5-hydroxyisoquinoline (249 mg, 1.72 mmol, 1.5 equiv., commerciallyavailable from the Aldrich Chemical Company) in dry toluene (17 mL) andstir at room temperature overnight. The reaction mixture is concentratedunder reduced pressure and the crude residue thus obtained is purifiedvia medium pressure liquid chromatography eluting with 1:1 ethylacetate:hexanes to afford the title compound as a yellow solid (298 mg,67%): δ_(H) (CDCl₃, 400 MHz): 2.40-2.50 (m, 1H), 2.62-2.72 (m, 1H),3.25-3.35 (m, 1H), 3.38-3.48 (m, 1H), 5.50 (dd, 1H, J=8,4 Hz), 6.73 (d,1H, J=8 Hz), 7.23-7.49 (m, 7H), 7.66 (d, 1H, J=8 Hz), 8.73 (d, 1H, J=9Hz), 8.92 (dd, 1H, J=4, 2 Hz).

In the following section, there is described the synthesis of compoundsof the present invention.

EXAMPLE 1 [(3R)-3-(Isoquinolin-4-yloxy)-3-phenyl-propyl]-methyl-aminehydrochloride

Add methyl amine (3 mL, 40% wt in water) to a solution of4-[(3R)-chloro-1-phenyl-propoxy]-isoquinoline (163 mg, 0.546 mmol) in1,4-dioxane (7 mL) in a heavy walled screw top sealed tube, seal thetube, and heat at 110° C. overnight. The mixture is cooled andconcentrated under reduced pressure. Purification by medium pressureliquid chromatography eluting with 0-5% of 2N NH₃/MeOH indichloromethane is followed by HCl salt formation by dissolving inmethanol (5 mL), adding solid ammonium chloride (23.4 mg, 0.437 mmol,)and sonicating for 15-20 minutes. The mixture is concentrated underreduced pressure and the residue is dissolved in water, frozen at −78°C., and freeze dried to afford the title compound as a colorless solid(143 mg, 80%): δ_(H) (CDCl₃, 400 MHz): 2.50-2.62 (m, 1H), 2.67 (s, 3H),2.70-2.81 (m, 1H), 3.17-3.27 (m, 2H), 5.75 (dd, 1H, J=8, 5 Hz),7.19-7.30 (m, 3H), 7.41 (d, 2H, J=6 Hz), 7.59 (dd, 1H, J=7,7 Hz), 7.74(dd, 1H, J=8, 8 Hz), 7.84 (d, 1H, J=8 Hz), 7.93 (s, 1H), 8.32 (d, 1H,J=8 Hz), 8.73 (s, 1H), 9.88 (br s, 2H).

Similarly prepared were

EXAMPLE 2 [(3R)-3-(Isoquinolin-6-yloxy)-3-phenyl-propyl]-methyl-aminehydrochloride

as an off-white solid (172 mg, 40%): δ_(H) (CDCl₃, 400 MHz): 2.43-2.63(m, 2H), 2.66 (s, 3H), 3.10-3.25 (m, 2H), 5.62 (dd, 1H, J=8, 4 Hz), 6.91(d, 1H, J=2 Hz), 7.20-7.43 (m, 7I1), 7.78 (d, 1H, J=10 Hz), 8.32 (d, 1H,J=6 Hz), 9.01 (s, 1H).

EXAMPLE 3Methyl-[(3R)-3-([1,7]naphthyridin-5-yloxy)-3-phenyl-propyl]-aminehydrochloride

as a solid (175 mg, 32%): δ_(H) (CDCl₃, 400 MHz): 2.50-2.65 (m, 1H),2.68-2.82 (m, 1H), 2.69 (s, 3H), 3.15-3.30 (m, 2H), 5.79 (dd, 1H, J=8, 5Hz), 7.20-7.33 (m, 3H), 7.37-7.47 (m, 2H), 7.61 (dd, 1H, J=9, 4 Hz),8.06 (br s, 1H), 8.66 (dd, 1H, J=9, 1 Hz), 8.98 (dd, 1H, J=4, 1 Hz),9.00 (br s, 1H), 9.83 (br s 2H).

EXAMPLE 4 [(3R)-3-(Isoquinolin-5-yloxy)-3-phenyl-propyl]-methyl-aminehydrochloride

as a solid (211 mg, 50%): δ_(H) (CDCl₃, 400 MHz): 2.50-2.63 (m, 1H),2.64-2.80 (m, 1H), 2.67 (s, 3H), 3.15-3.30 (m, 2H), 5.69 (dd, 1H, J=8, 5Hz), 6.86 (d, 1H, J=8 Hz), 7.20-7.33 (m, 4H), 7.38 (d, 2H, J=7 Hz), 7.45(d, 1H, J=8 Hz), 8.16 (br s, 1H), 8.53 (br s, 1H), 9.20 (br s, 1H), 9.85(br s, 2H).

EXAMPLE 5 Methyl-[(3R)-3-phenyl-3-(quinolin-5-yloxy)-propyl]-aminehydrochloride

as a solid (149 mg, 71%): δ_(H) (CDCl₃, 400 MHz): 2.51-2.78 (m, 2H),2.64 (s, 3H), 3.15-27 (m, 2H), 5.63 (dd, 1H, J=8, 4 Hz), 6.70 (d, 1H,J=8 Hz), 7.20-7.50 (m, 7H), 7.63 (d, 1H, J=9 Hz), 8.74 (d, 1H,J=8 Hz),8.84(br d, 1H, J=3 Hz), 9.82 (br s, 2H).

EXAMPLE 6(3R)-[3-(4-Fluoro-2,3-dihydrobenzo[b]thiopohen-7-yloxy)-3-phenylpropyl]-methyl-aminehydrochloride

Prepared similarly except the aqueous methyl amine (40 wt %) was stirredat room temperature with(1R)-4-fluoro-7-(3-iodo-1-phenyl-propoxy)-2,3-dihydrobenzo[b]thiophenein THF. The hydrochloride salt was formed by addition of 1M hydrochloricacid in diethyl ether (1 eq) to a solution of the compound in diethylether. Filtration of the solid gave 111 mg of a white crystalline solid:δ_(H) (300 MHz, CDCl₃) 9.61 (1H, br. s, NH), 7.41-7.20 (5H, m, ArH),6.51-6.32 (2H, m, ArH), 5.40-5.32 (1H, m, CHO), 3.47-3.25 (4H, m,SCH₂CH₂), 3.25-3.15 (2H, m, 1-CH₂), 2.70 (3H, s, NHCH₃) and 2.58-2.31(2H, m, 2-CH₂).

Prepared similarly was

EXAMPLE 7

(3S)-[3-(4-Fluoro-2,3-dihydrobenzo[b]thiophen-7-yloxy-3-phenylpropyl]-methyl-aminehydrochloride

to give 101 mg of a white crystalline solid; δ_(H) (300 MHz, CDCl₃) 9.61(1H, br. s, NH), 7.41-7.20 (5H, m, ArH), 6.51-6.32 (2H, m, ArH),5.40-5.32 (1H, m, CHO), 3.47-3.25 (4H, m, SCH₂CH₂), 3.25-3.15 (2H, m,1-CH₂), 2.70 (3H, s, NHCH₃) and 2.58-2.31 (2H, m, 2-CH₂).

EXAMPLE 8(3R)-3-(1,3-Benzothiazol-4-yloxy)-N-methyl-3-phenyl-propan-1-amine

To a stirred suspension of(3R)-3-(1,3-benzothiazol-4-yloxy)-N-methyl-3-phenyl-N-(phenylmethyl)-propan-1-amine(0.18 g, 0.463 mmol) in dry DCM (10 ml) and Polymer supporteddiethylamine [PS-DIEA] (0.39g, 3.56 mmol/g, 1.38 mmol) was added1-chloroethyl chloroformate (0.25 ml, 2.3 mmol), the resultingsuspension was heated to reflux for 2 hours. The reaction mixture wasallowed to cool to room temperature and the PS-DIEA was removed byfiltration. The reaction mixture was concentrated in vacuo, with theresidue being re-dissolved in MeOH (10 ml) and heated to reflux for afurther 4 hours. After this time the reaction was concentrated in vacuoand purified by flash chromatography eluting silica gel with DCM:MeOH[9:1] to give the free base (136 mg, 98%). R_(f)=0.36 [9:1] DCM:MeOH:δ_(H) (300 MHz, CDCl₃) 9.07 (1H, s, Ar), 7.60-6.66 (8H, m, Ar), 5.39(1H,dd, CHO), 3.49-3.45 (1H, m, CHH), 3.31-3.20 (1H, m, CHH), 2.88 (3H, s,CH₃), 2.68-2.62 (1H, m, CHH), 2.51-2.47 (1H, m, CHH).

EXAMPLE 9Methyl-[(3R)-3-phenyl-3-(thieno[3,2-b]pyridin-7-yloxy)-propyl]-aminehydrochloride

Methylamine (40% in water, 7 ml) was added to a solution of7-[(1R)-(3-Iodo-1-phenyl-propoxy)]-thieno[3,2-b]pyridine (110 mg, 0.28mmol) in EtOH (5 ml), the resulting solution was stirred at rt for 4 h.The solvent was removed in vacuo and the residue was purified by flashchromatography eluting silica gel with CH₂Cl₂: MeOH (2M NH₃) [100:0 to10:1] to yield the free-base of the title compound (153 mg, 77%). Theresulting residue was dissolved in MeOH (5 mL) and NH₄Cl was added. Themixture was sonicated at room temperature for 10 min and then thesolvent removed in vacuo. The residue was dissolved in MeCN (0.5 mL) andwater (1 mL), this solution was then frozen by immersion in a dryice:acetone bath, the resulting frozen material was freeze driedovernight to yield the target compound as a fluffy white solid: Meltingpoint of title compound: 120.4° C.

Prepared similarly were

EXAMPLE 10Methyl-[(3S)-3-phenyl-3-(thieno[3,2-b]pyridin-7-yloxy)-propyl]-aminehydrochloride

to afford the title compound (120 mg, 80%); Melting point: 118.2° C.

EXAMPLE 11Methyl-[(3S)-3-phenyl-3-(thieno[3,2-c]pyridin-7-yloxy)-propyl]-aminehydrochloride

(R)-(+)-3-iodo-1-phenyl-1-propanol (0.68 g, 2.6 mmol) andthieno[3,2-c]pyridin-7-ol (0.30 g, 1.98 mmol) in dry THF (8 ml) werestirred under an inert atmosphere of nitrogen. Merck Reagent(4,4-(dimethyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)-triphenylphosphonium) (1.06 g, 2.6 mmol) was added and the resulting suspensionwas allowed to stir for a further 120 h at rt before the solvent wasremoved in vacuo. The residue was purified by flash chromatography,eluting silica gel with hexane: ethyl acetate [100:0 to 1:1] to yieldthe intermediate iodo compound (0.183 g, 23%). This residue wasimmediately taken up in 10 mL of 2M NH₃ in THF and stirred for 4 h. Thesolvent was removed in vacuo and the residue was purified by flashchromatography eluting silica gel with CH₂Cl₂: MeOH (2M NH₃) [100:0 to3:1] to yield the free-base of the title compound (29.2 mg, 22%). Theresulting residue was dissolved in MeOH (5 mL) and NH₄Cl was added. Themixture was sonicated at room temperature for 10 min and then thesolvent removed in vacuo. The residue was dissolved in MeCN (0.5 mL) andwater (1 mL), this solution was then frozen by immersion in a dryice:acetone bath, the resulting frozen material was freeze driedovernight to yield the target compound as a fluffy white solid: massspectrum (ion spray): m/z=299.12 (m+1).

Prepared similarly were

EXAMPLE 12 Methyl-[(3R )3-phenyl-3-(thieno[3,2-c]pyridin-7-yloxy)-propyl]-amine hydrochloride

gave the title compound (49.5 mg, 41%); mass spectrum (ion spray):m/z=299.12 (m+1).

EXAMPLE 13Methyl-[(3R)-3-phenyl-3-(thieno[2,3-c]pyridin-4-yloxy)-propyl]-aminehydrochloride

gave the title compound as a solid (38 mg, 29%): Melting point: 68.1° C.

EXAMPLE 14(S)-[3-(Benzo[d]isothiazol-4-yloxy)-3-phenyl-propyl]-methyl-aminehydrochloride

gave the title compound (206 mg, 62%): Mass spectrum (ion-spray):m/z=299.1 (m+1).

EXAMPLE 15(R)-[3-(Benzo[d]isothiazol-7-yloxy)-3-phenyl-propyl]-methyl-aminehydrochloride

gave the title compound (17 mg, 22%); Mass spectrum (ion-spray):m/z=299.1 (m+1).

EXAMPLE 16(S)-[3-(Benzo[d]isothiazole-7-yloxy)-3-phenyl-propyl]-methyl-aminehydrochloride

gave the title compound (85 mg, 50%); Mass spectrum (ion-spray):m/z=299.1 (m+1).

EXAMPLE 17(R)-Methyl-[3-(7-methyl-benzo[d]isothiazol-4-yloxy)-3-phenyl-propyl]-aminehydrochloride

gave the title compound (77 mg, 32%); Mass spectrum (ion-spray):m/z=313.1 (M+1).

EXAMPLE 18(S)-Methyl-[3-(7-methyl-benzo[d]isothiazol-4-yloxy)-3-phenyl-propyl]-aminehydrochloride

gave the title compound (71 mg, 34%); Mass spectrum (ion-spray):m/z=313.1 (m+1).

EXAMPLE 19 [(3S)-3-(Isoquiolin-4-yloxy)-3-phenyl-propyl]-methyl-aminehydrochloride

Add methyl amine (3 mL, 40% wt in water) to a solution of4-[(3S)-chloro-1-phenyl-propoxy]-isoquinoline (229 mg, 0.769 mmol) in1,4-dioxane (10 mL) in a heavy walled screw top sealed tube, seal thetube, and heat at 110° C. overnight. The mixture is cooled andconcentrated under reduced pressure. Purification by medium pressureliquid chromatography eluting with 0-4% of 2N NH₃/MeOH indichloromethane is followed by HCl salt formation by dissolving inmethanol (3 mL), adding solid ammonium chloride (30.8 mg, 0.576 mmol,)and sonicating for 15-20 minutes. The mixture is concentrated underreduced pressure and the residue is dissolved in water, frozen at −78°C., and freeze dried to afford the title compound as a colorless solid(185 mg, 73%): δ_(H) (CDCl₃, 400 MHz): 2.50-2.62 (m, 1H), 2.67 (s, 3H),2.70-2.81 (m, 1H), 3.17-3.27 (m, 2H), 5.75 (dd, 1H, J=8, 5 Hz),7.19-7.30 (m, 3H), 7.41 (d, 2H, J=6 Hz), 7.59 (dd, 1H, J=7, 7 Hz), 7.74(dd, 1H, J=8, 8 Hz), 7.84 (d, 1H, J=8 Hz), 7.93 (s, 1H), 8.32 (d, 1H,J=8 Hz), 8.73 (s, 1H), 9.88 (br s, 2H).

Similarly prepared were

EXAMPLE 20 [(3S)-3-(Isoquinolin-6-yloxy)-3-phenyl-propyl]-methyl-aminehydrochloride

as an off-white solid (270 mg, 37%): δ_(H) (CDCl₃, 400 MHz): 2.43-2.63(m, 2H), 2.66 (s, 3H), 3.10-3.25 (m, 2H), 5.62 (dd, 1H, J=8,4 Hz), 6.91(d, 1H, J=2 Hz), 7.20-7.43 (m, 7H), 7.78 (d, 1H, J=10 Hz), 8.32 (d, 1H;J=6 Hz), 9.01 (s, 1).

EXAMPLE 21 [(3S)-3-(Isoquinolin-5-yloxy)-3-phenyl-propyl]-methyl-aminehydrochloride

as a solid (358 mg, 98%): δ_(H) (CDCl₃, 400 MHz): 2.50-2.63 (m, 1H),2.64-2.80 (m, 1H), 2.67 (s, 3), 3.15-3.30 (m, 2H), 5.69 (dd, 1H, J=8, 5Hz), 6.86 (d, 1H, J=8 Hz), 7.20-7.33 (m, 411), 7.38 (d, 2H, J=7 Hz),7.45 (d, 1H, J=8 Hz), 8.16 (br s, 1H), 8.53 (br s, 1H), 9.20 (br s, 1H),9.85 (br s, 2H).

EXAMPLE 22 Methyl-[(3S)-3-phenyl-3-(quinolin-5-yloxy)-propyl]-aminehydrochloride

Add methyl amine (40% wt in water, 5 mL) to a solution of5-[(3S)-iodo-1-phenyl-propoxy]-quinoline quinoline (200 mg, 0.51 mmol, 1equiv.) in THF (1mL) and stir at room temperature for 1 hr. The reactionmixture is concentrated under reduced pressure and purified by mediumpressure liquid chromatography eluting with 0-8% of 2N NH₃/MeOH indichloromethane which is followed by HCl salt formation by dissolving inmethanol, adding solid ammonium chloride (9.5 mg, 0.18 mmol) andsonicating for 15-20 minutes. The mixture is concentrated under reducedpressure and the residue is dissolved in water, frozen at −78° C., andfreeze dried to afford the title compound as a solid (65 mg, 35 %):δ_(H) (CDCl₃, 400 MHz): 2.51-2.78 (m, 2H), 2.64 (s, 3H), 3.15-3.27 (m,2H), 5.63 (dd, 1H, J=8, 4 Hz), 6.70 (d, 1H, J=8 Hz), 7.20-7.50 (m, 7H),7.63 (d, 1H, J=9 Hz), 8.74 (d, 1H, J=8 Hz), 8.84 (br d, 1H, J=3 Hz),9.82 (br s, 2H).

The compounds of the present invention may be used as medicaments inhuman or veterinary medicine. The compounds may be administered byvarious routes, for example, by oral or rectal routes, topically orparenterally, for example by injection, and are usually employed in theform of a pharmaceutical composition.

Such compositions may be prepared by methods well known in thepharmaceutical art and normally comprise at least one active compound inassociation with a pharmaceutically acceptable diluent or carrier. Inmaking the compositions of the present invention, the active ingredientwill usually be mixed with a carrier or diluted by a carrier, and/orenclosed within a carrier which may, for example, be in the form of acapsule, sachet, paper or other container. Where the carrier serves as adiluent, it may be solid, semi-solid, or liquid material which acts as avehicle, excipient or medium for the active ingredient. Thus, thecomposition may be in the form of tablets, lozenges, sachets, cachets,elixirs, suspensions, solutions, syrups, aerosol (as a solid or in aliquid medium), ointments containing, for example, up to 10% by weightof the active compound, soft and hard gelatin capsules, suppositories,injection solutions and suspensions and sterile packaged powders.

Some examples of suitable carriers are lactose, dextrose, vegetableoils, benzyl alcohols, alkylene glycols, polyethylene glycols, glyceroltriacetate, gelatin, carbohydrates such as starch and petroleum jelly,sucrose sorbitol, mannitol, starches, gum acacia,calcium phosphate,alginates, tragacanth, gelatin, syrup, methyl cellulose, methyl- andpropyl-hydrobenzoate, talc, magnesium stearate and mineral oil. Thecompounds of formula (I) can also be lyophilized and the lyophilizatesobtained used, for example, for the production of injectionpreparations. The preparations indicated can be sterilized and/or cancontain auxiliaries such as lubricants, preservatives, stabilizersand/or wetting agents, emulsifiers, salts for affecting the osmoticpressure, buffer substances, colourants, flavourings and/or one or morefurther active compounds, e.g. one or more vitamins. Compositions of theinvention may be formulated so as to provide, quick, sustained ordelayed release of the active ingredient after administration to thepatient by employing procedures well known in the art.

The compositions are preferably formulated in a unit dosage form, eachdosage containing from about 5 to about 500 mg, more usually about 25 toabout 300 mg, of the active ingredient. The term “unit dosage form”refers to physically discrete units suitable as unitary doses for humansubjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, in association with a suitable pharmaceuticalcarrier.

The pharmacological profile of the present compounds may be demonstratedas follows. Preferred compounds of the present invention exhibit a K_(i)value less than 1 μM at the serotonin and norepinephrine transporters asdetermined using the scintillation proximity assays described below.More preferred compounds of the present invention exhibit a K_(i) valueless than 100 nM at the serotonin transporter and/or a K_(i) value lessthan 100 nM at the norepinephrine transporter as determined using thescintillation proximity assays described below. Stil more preferredcompounds of the present invention are those which exhibit a K_(i) valueless than 100 nM (preferably less than 50 nM) at the serotonintransporter and a K_(i) value less than 100 nM (preferably less than 50nM) at the norepinephrine transporter as determined using thescintillation proximity assays described below. Furthermore, preferredcompounds of the present invention selectively inhibit the serotonin andnorepinephrine transporters relative to the dopamine transporter by afactor of at least five using the scintillation proximity assays asdescribed below.

Generation of Stable Cell-Lines Expressing the Human Dopamine,Norepinephrine and Serotonin Transporters

Standard molecular cloning techniques were used to generate stablecell-lines expressing the human dopamine, norepinephrine and serotonintransporters. The polymerase chain reaction (PCR) was used in order toisolate and amplify each of the three full-length cDNAs from anappropriate cDNA library. Primers for PCR were designed using thefollowing published sequence data:

Human dopamine transporter: GenBank M95167. Reference: Vandenbergh D J,Persico A M and Uhl G R. A human dopanmine transporter cDNA predictsreduced glycosylation, displays a novel repetitive element and providesracially-dimorphic TaqI RFLPs. Molecular Brain Research (1992) volume15, pages 161-166.

Human norepinephrine transporter: GenBank M65105. Reference: PacholczykT, Blakely, R D and Amara S G. Expression cloning of a cocaine- andantidepressant-sensitive human noradrenaline transporter. Nature (1991)volume 350, pages 350-354.

Human serotonin transporter: GenBank L05568. Reference: Ramamoorthy S,Bauman A L, Moore K R, Han H, Yang-Peng T, Chang A S, Ganapathy V andBlakely R D. Antidepressant- and cocaine-sensitive human serotonintransporter: Molecular cloning, expression, and chromosomallocalization. Proceedings of the National Academy of Sciences of the USA(1993) volume 90, pages 2542-2546.

The PCR products were cloned into a mammalian expression vector (egpcDNA3.1 (Invitrogen)) using standard ligation techniques. Theconstructs were then used to stably transfect HEK293 cells using acommercially available lipofection reagent (Lipofectamine™—Invitrogen)following the manufacture's protocol.

Scintillation Proximity Assays for Determining the Affinity of TestLigands at the Norepinephrine and Serotonin Transporters.

The compounds of the present invention are norepinephrine and serotoninreuptake inhibitors, and possess excellent activity in, for example, ascintillation proximity assay (e.g. J. Gobel, D. L. Saussy and A. Goetz,J. Pharmacol. Toxicolo. (1999), 42, 237-244). Thus ³H-nisoxetine bindingto norepinephrine re-uptake sites in a cell line transfected with DNAencoding human norepinephrine transporter binding protein and similarly³H-citalopram binding to serotonin re-uptake sites in a cell linetransfected with DNA encoding human serotonin transporter bindingprotein have been used to determine the affinity of ligands at thenorepinephrine and serotonin transporters respectively.

Norepinephrine Binding Assay

Membrane Preparation:

Cell pastes from large scale production of HEK-293 cells expressingcloned human norepinephrine transporters were homogenized in 4 volumes50 mM Tris-HCl containing 300 mM NaCl and 5 mM KCl, pH 7.4. Thehomogenate was centrifuged twice (40,000 g, 10 min, 4° C.) with pelletre-suspension in 4 volumes of Tris-HCl buffer containing the abovereagents after the first spin and 8 volumes after the second spin. Thesuspended homogenate was centrifuged (100 g, 10 min, 4° C.) and thesupernatant kept and recentrifuged (40,000 g, 20 min, 4° C.). The pelletwas resuspended in Tris-HCl buffer containing the above reagents alongwith 10% w/v sucrose and 0.1 mM phenylmethylsulfonyl fluoride (PMSF).The membrane preparation was stored in aliquots (1 ml) at −80° C. untilrequired. The protein concentration of the membrane preparation wasdetermined using a bicinchoninic acid (BCA) protein assay reagent kit(available from Pierce).

[³H]-Nisoxetine Binding Assay:

Each well of a 96 well microtitre plate was set up to contain thefollowing:

50 μl 2 nM [N-methyl-³H]-Nisoxetine hydrochloride (70-87 Ci/mmol, fromNEN Life Science Products)

75 μl Assay buffer (50 mM Tris-HCl pH 7.4 containing 300 mM NaCl and 5mM KCl)

25 μl Test compound, assay buffer (total binding) or 10 μM DesipramineHCl (non-specific binding)

50 μl Wheatgerm agglutinin coated poly (vinyltoluene) (WGA PVT) SPABeads (Amersham Biosciences RPNQ0001) (10 mg/ml)

50 μl Membrane (0.2 mg protein per ml)

The microtitre plates were incubated at room temperature for 10 hoursprior to reading in a Trilux scintillation counter. The results wereanalysed using an automatic spline fitting programme (Multicalc,Packard, Milton Keynes, UK) to provide Ki values for each of the testcompounds.

Serotonin Binding Assay

The ability of a test compound to compete with [³H]-citalopram for itsbinding sites on cloned human serotonin transporter containing membraneshas been used as a measure of test compound ability to block serotoninuptake via its specific transporter (Ramamoorthy, S., Giovanetti, E.,Qian, Y., Blakely, R., (1998) J. Biol. Chem. 273, 2459).

Membrane Preparation:

Membrane preparation is essentially similar to that for thenorepinephrine transporter containing membranes as described above. Themembrane preparation was stored in aliquots (1 ml) at −70° C. untilrequired. The protein concentration of the membrane preparation wasdetermined using a BCA protein assay reagent kit.

[³H]-Citalopram Binding Assay:

Each well of a 96 well microtitre plate was set up to contain thefollowing:

50 μl 2 nM [³H]-Citalopram (60-86 Ci/mmol, Amersham Biosciences)

75 μl Assay buffer (50 mM Tris-HCl pH 7.4 containing 150 mM NaCl and 5mM KCl)

25 μl Diluted compound, assay buffer (total binding) or 100 μMFluoxetine (non-specific binding)

50 μl WGA PVT SPA Beads (40 mg/ml)

50 μl Membrane preparation (0.4 mg protein per ml)

The microtitre plates were incubated at room temperature for 10 hoursprior to reading in a Trilux scintillation counter. The results wereanalysed using an automatic spline fitting programme (Multicalc,Packard, Milton Keynes, UK) to provide Ki (nM) values for each of thetest compounds.

Dopamine Binding Assay

The ability of a test compound to compete with [³H]-WIN35,428 for itsbinding sites on human cell membranes containing cloned human dopaminetransporter has been used as a measure of the ability of such testcompounds to block dopamine uptake via its specific transporter(Ramamoorthy et al 1998 supra).

Membrane Preparation:

Is essentially the same as for membranes containing cloned humanserotonin transporter as described above.

[³H]-WIN35,428 Binding Assay:

Each well of a 96well microtitre plate was set up to contain thefollowing:

50 μl 4 nM [³H]-WIN35,428 (84-87 Ci/mmol, from NEN Life ScienceProducts) 75 μl Assay buffer (50 nM Tris-HCI pH 7.4 containing 150 mMNaCl and 5 mM KCl)

25 μl Diluted compound, assay buffer (total binding) or 100 μMNomifensine (non-specific binding)

50 μl WGA PVT SPA Beads (10 mg/ml)

50 μl Membrane preparation (0.2 mg protein per ml.)

The microtitre plates were incubated at room temperature for 120 minutesprior to reading in a Trilux scintillation counter. The results wereanalysed using an automatic spline fitting programme (Multicalc,Packard, Milton Keynes, UK) to provide Ki values for each of the testcompounds.

Formalin Paw Assay

The analgesic effect of compounds of the invention for the treatment ofpersistent nociceptive pain was demonstrated using the well-known“formalin test.” The formalin test is a model of persistent nociceptiveactivation induced by tissue injury which can lead to centralsensitization. (Shibata, M., Ohkubo, T., Takahashi, H., and Inoki, R.,“Modified formalin test: Characteristic biphasic pain response,” Pain(1989) 38: 347-352; and Tjolsen, A., Berge, O. G., Hunskaar, S.,Rosland, J. H., and Hole, K., “The formalin test: an evaluation of themethod,” Pain (1992) 51:5-17.) The effect of compounds of the inventionon formalin-induced paw-licking behavior in the rat was investigated asan index of persistent nociceptive activation. In this test, theinjection of formalin under the skin on the dorsal lateral surface ofthe hind paw of rats causes an immediate and intense increase in thespontaneous activity of C fiber afferents. This activation evokes adistinctly quantifiable behavior indicative of pain, such as licking ofthe injected paw. The behavioral response to formalin is biphasic, withan early phase that is short lived, followed by an extended tonicresponse or late phase of persistent nociceptive activation. Mechanismscausing the late phase response, such as central sensitization of paintransmitting neurons, are currently believed to contribute to varioustypes of persistent pains.

Male Sprague-Dawley rats (200-250 g; Charles River, Portage, Md. weremaintained at constant temperature and light (12 h light/12 h dark) for4-7 days prior to the studies. Animals had free access to food and waterat all times prior to the day of the experiment.

Scoring in the formalin test was performed according to Coderre et al.,1993b and Abbott et al., 1995. (Coderre T. J., Fundytus M. E., McKennaJ. E., Dalal S. and Melzack R. “The formalin test: a validation of theweighted-scores method of the behavioral pain rating,” Pain(1993b) 54:43-50; and Abbott F. V., Franklin K. B. J. and Westbrook R. F. “Theformalin test: scoring properties of the first and second phases of thepain response in rats,” Pain (1995) 60: 91-102.) The sum of time spentlicking in seconds from time 0 to 5 minutes was considered the earlyphase while the late phase was taken as the sum of seconds spent lickingfrom 15 to 40 minutes.

Data are presented as means with standard errors of means (±SEM). Datawere evaluated by one-way analysis of variance (ANOVA) and theappropriate contrasts analyzed by Tukey's test and Dunnett “t” test fortwo-sided comparisons.

The preferred compounds of the present invention show good stability tothe action of the CYP 2D6 enzyme. This is advantageous because it islikely to lead to improved metabolic stability of the compounds.

Stability to the CYP 2D6 enzyme may be determined according to the assaydescribed below:

In Vitro Determination of the Interaction of Compounds with CYP2D6 inHuman Hepatic Microsomes

Cytochrome P450 2D6 (CYP2D6) is a mammalian enzyme which is commonlyassociated with the metabolism of around 30% of pharmaceuticalcompounds. Moreover, this enzyme shows a genetic polymorphism with as aconsequence a presence in the population of poor and normalmetabolizers. A low involvement of CYP2D6 in the metabolism of compounds(i.e. the compound being a poor substrate of CYP2D6) is desirable inorder to reduce any variability from subject to subject in thepharmacokinetics of the compound. Also, compounds with a low inhihibitorpotential for CYP2D6 are desirable in order to avoid drug-druginteractions with co-administered drugs that are substrates of CYP2D6.Compounds may be tested both as substrates and as inhibitors of thisenzyme by means of the following assays.

CYP2D6 Substrate Assay

Principle:

This assay determines the extent of the CYP2D6 enzyme involvement in thetotal oxidative metabolism of a compound in microsomes. Preferredcompounds of the present invention exhibit less than 75% totalmetabolism via the CYP2D6 pathway.

For this in vitro assay, the extent of oxidative metabolism in humanliver microsomes (HLM) is determined after a 30 minute incubation in theabsence and presence of Quinidine, a specific chemical inhibitor ofCYP2D6. The difference in the extent of metabolism in absence andpresence of the inhibitor indicates the involvement of CYP2D6 in themetabolism of the compound.

Materials and Methods:

Human liver microsomes (mixture of 20 different donors, mixed gender)were acquired from Human Biologics (Scottsdale, Ariz., USA). Quinidineand β-NADPH (β-Nicotinamide Adenine Dinucleotide Phosphate, reducedform, tetrasodium salt) were purchased from Sigma (St Louis, Mo., USA).All the other reagents and solvents were of analytical grade. A stocksolution of the new chemical entity (NCE) was prepared in a mixture ofAcetonitrile/Water to reach a final concentration of acetonitrile in theincubation below 0.5%.

The microsomal incubation mixture (total volume 0.1 mL) contained theNCE (4 μM), β-NADPH (1 mM), microsomal proteins (0.5 mg/mL), andQuinidine (0 or 2 μM) in 100 mM sodium phosphate buffer pH 7.4. Themixture was incubated for 30 minutes at 37° C. in a shaking waterbath.The reaction was terminated by the addition of acetonitrile (75 μL). Thesamples were vortexed and the denaturated proteins were removed bycentrifugation. The amount of NCE in the supernatant was analyzed byliquid chromatography/mass spectrometry (LC/MS) after addition of aninternal standard. A sample was also taken at the start of theincubation (t=0), and analysed similarly.

Analysis of the NCE was performed by liquid chromatography /massspectrometry. Ten μL of diluted samples (20 fold dilution in the mobilephase) were injected onto a Spherisorb CN Column, 5 μM and 2.1 mm×100 mm(Waters corp. Milford, Mass., USA). The mobile phase consisting of amixture of Solvent A/Solvent B, 30/70 (v/v) was pumped (Alliance 2795,Waters corp. Milford, Mass., USA) through the column at a flow rate of0.2 ml/minute. Solvent A and Solvent B were a mixture of ammoniumformate 5.10 ⁻³ M pH 4.5/methanol in the proportions 95/5 (v/v) and10/90 (v/v), for solvent A and solvent B, respectively. The NCE and theinternal standard were quantified by monitoring their molecular ionusing a mass spectrometer ZMD or ZQ (Waters-Micromass corp, Machester,UK) operated in a positive electrospray ionisation.

The extent of CYP2D6 involvement (% of CYP2D6 involvement) wascalculated comparing the extent of metabolism in absence and in presenceof quinidine in the incubation.

The extent of metabolism without inhibitor (%) was calculated asfollows:$\frac{{\left( {{NCE}\quad\text{response~~in~~samples~~without~~inhibitor}} \right)\text{time}\quad 0} - {\left( {{NCE}\quad\text{response~~in~~samples~~without~~inhibitor}} \right)\text{time}\quad 30}}{\left( {{NCE}\quad\text{response~~in~~samples~~without~~inhibitor}} \right)\text{time}\quad 0} \times 100$

The extent of metabolism with inhibitor (%) was calculated as follows:$\frac{{\left( {{NCE}\quad\text{response~~in~~samples~~without~~inhibitor}} \right)\text{time}\quad 0} - {\left( {{NCE}\quad\text{response~~in~~samples~~with~~inhibitor}} \right)\text{time}\quad 30}}{\left( {{NCE}\quad\text{response~~in~~samples~~without~~inhibitor}} \right)\text{time}\quad 0} \times 100$where the NCE response is the area of the NCE divided by the area of theinternal standard in the LC/MS analysis chromatogram, time0 and time30correspond to the 0 and 30 minutes incubation time.

The % of CYP2D6 involvement was calculated as follows:$\frac{\left( {\%\quad\text{extent~~of~~metabolism~~without~~inhibitor}} \right) - \left( {\%\quad\text{extent~~of~~metabolism~~with~~inhibitor}} \right)}{\%\quad\text{extent~~of~~metabolism~~without~~inhibitor}} \times 100$CYP2D6 Inhibitor AssayPrinciple:

The CYP2D6 inhibitor assay evaluates the potential for a compound toinhibit CYP2D6. This is performed by the measurement of the inhibitionof the bufuralol 1′-hydroxylase activity by the compound compared to acontrol. The 1′-hydroxylation of bufuralol is a metabolic reactionspecific to CYP2D6. Preferred compounds of the present invention exhibitan IC₅₀ higher than 6 μM for CYP2D6 activity, the IC₅₀ being theconcentration of the compound that gives 50% of inhibition of the CYP2D6activity.

Material and Methods:

Human liver microsomes (mixture of 20 different donors, mixed gender)were acquired from Human Biologics (Scottsdale, Ariz.). β-NADPH waspurchased from Sigma (St Louis, Mo.). Bufuralol was purchased fromUltrafine (Manchester, UK). All the other reagents and solvents were ofanalytical grade.

Microsomal incubation mixture (total volume 0.1 mL) contained bufuralol10 μM, β-NADPH (2 mM), microsomal proteins (0.5 mg/mL), and the newchemical entity (NCE) (0, 5, and 25 μM) in 100 mM sodium phosphatebuffer pH 7.4. The mixture was incubated in a shaking waterbath at 37°C. for 5 minutes. The reaction was terminated by the addition ofmethanol (75 μL). The samples were vortexed and the denaturated proteinswere removed by centrifugation. The supernatant was analyzed by liquidchromatography connected to a fluorescence detector. The formation ofthe 1′-hydroxybufuralol was monitored in control samples (0 μM NCE) andin the samples incubated in presence of the NCE. The stock solution ofNCE was prepared in a mixture of Acetonitrile/Water to reach a finalconcentration of acetonitrile in the incubation below 1.0%.

The determination of 1′hydroxybufuralol in the samples was performed byliquid chromatograhy with fluorimetric detection as described below.Twenty five μL samples were injected onto a Chromolith PerformanceRP-18e column (100 mm×4.6 mm) (Merck KGAa, Darmstadt, Germany). Themobile phase, consisting of a mixture of solvent A and solvent B whosethe proportions changed according the following linear gradient, waspumped through the column at a flow rate of 1 ml/min: Time (minutes)Solvent A (%) Solvent B (%) 0 65 35 2.0 65 35 2.5 0 100 5.5 0 100 6.0 6535

Solvent A and Solvent B consisted of a mixture of 0.02 M potassiumdihydrogenophosphate buffer pH3/methanol in the proportion 90/10 (v/v)for solvent A and 10/90 (v/v) for solvent B. The run time was 7.5minutes. Formation of 1′-hydroxybufuralol was monitored by fluorimetricdetection with extinction at λ 252 nm and emission at λ 302 nm.

The IC₅₀ of the NCE for CYP2D6 was calculated by the measurement of thepercent of inhibition of the formation of the 1′-hydroxybufuralol inpresence of the NCE compared to control samples (no NCE) at a knownconcentration of the NCE.

The percent of inhibition of the formation of the 1′-hydroxybufuralol iscalculated as follows:$\frac{\left( {{1'}\text{-hydroxybufuralol~~formed~~without~~inhibitor}} \right) - \left( {{1'}\text{-hydroxybufuralol~~formed~~with~~inhibitor}} \right)}{\left( {{1'}\text{-hydroxybufuralol~~area~~formed~~without~~inhibitor}} \right)} \times 100$

The IC₅₀ is calculated from the percent inhibition of the formation ofthe 1′-hydroxyfururalol as follows (assuming competitive inhibition):$\frac{{NCE}\quad\text{Concentration} \times \left( {100 - \text{Percent~~of~~inhibition}} \right)}{\text{Percent~~of~~inhibition}}$

The IC₅₀ estimation is assumed valid if inhibition is between 20% and80% (Moody G C, Griffin S J, Mather A N, McGinnity D P, Riley R J. 1999.Fully automated analysis of activities catalyzed by the major humanliver cytochrome P450 (CYP) enzymes: assessment of human CYP inhibitionpotential. Xenobiotica, 29(1): 53-75).

1. A compound of formula I

wherein A is selected from O and S; X is selected from phenyl optionallysubstituted with up to 5 substituents each independently selected fromhalo, C₁-C₄ alkyl and C₁-C₄ alkoxy; thienyl optionally substituted withup to 3 substituents each independently selected from halo and C₁-C₄alkyl; and C₂-C₈ alkyl, C₂-C₈ alkenyl, C₃-C₈ cycloalkyl and C₄-C₈cycloalkylalkyl, each of which may be optionally substituted with up to3 substituents each independently selected from halo, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ alkyl-S(O)_(n)— where n is 0, 1 or 2, —CF₃, —CN and—CONH₂; Y is selected from dihydrobenzothienyl, benzothiazolyl,benzoisothiazolyl, quinolyl, isoquinolyl, naphthyridyl, andthienopyridyl, each of which may be optionally substituted with up to 4or, where possible, up to 5 substituents each independently selectedfrom halo, C₁-C₄ alkyl, C₁- C₄ alkoxy, C₁-C₄ alkyl-S(O)_(n)— where n is0, 1 or 2, nitro, acetyl, —CF₃, —SCF₃ and cyano; Z is selected from H.OR₃ or F, wherein R₃ is selected from H, C₁-C₆ alkyl and phenyl C₁-C₆alkyl; R₁ and R₂ are each independently H or C₁-C₄ alkyl; orpharmaceutically acceptable salt thereof.
 2. A compound as claimed inclaim 1, wherein A is
 0. 3. A compound as claimed in claim 1, wherein Ais S.
 4. A compound as claimed in any one of claims 1-3, wherein one ofR₁ and R₂ is H.
 5. A compounds as claimed in any one of claims 1-3,wherein one of R₁ and R₂ is H and the other is methyl.
 6. A compound asclaimed in any one of claims 1-3, wherein the compound possesses thestereochemistry defined in formula


7. A compound as claimed in claim 6, wherein the compound possesses thestereochemistry defined in formula III


8. A compound as claimed in claim 5 wherein Z is H.
 9. A compound asclaimed in claim 5, wherein X is unsubstituted phenyl or phenyl which ismono-, di- or tri-substituted with substituents independently selectedfrom halo, C₁ -C₄ alkyl and C₁-C₄ alkoxy.
 10. A compound as claimed inclaim 9, wherein X is unsubstituted phenyl or phenyl which ismono-substituted with fluorine.
 11. A compound as claimed in claim 5,wherein Y is dihydrobenzothienyl optionally substituted with up to 5substituents each independently selected from halo, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ alkyl-S(O)_(n)— where n is 0, 1 or 2, nitro, acetyl, —CF₃,—SCF₃ and cyano.
 12. A compound as claimed in claim 11, wherein Y isunsubstituted dihydrobenzothienyl or dihydrobenzothienyl which ismono-substituted with fluorine.
 13. A compound as claimed in claim 10,wherein Y is benzothiazolyl or benzoisothiazolyl, each of which may beoptionally substituted with up to 4 substituents each independentlyselected from halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ alkyl-S(O)_(n)—where n is 0, 1 or 2, nitro, acetyl, —CF₃, —SCF₃ and cyano.
 14. Acompound as claimed in claim 13, wherein Y is unsubstitutedbenzothiazolyl, unsubstituted benzoisothiazolyl, benzothiazolyl which ismono-substituted with CH₃ or benzoisothiazolyl which is mono-substitutedwith CH₃.
 15. A compound as claimed in claim 10 , wherein Y isthienopyridyl optionally substituted with up to 4 substituents eachindependently selected from halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄alkyl-S(O)_(n)— where n is 0, 1 or 2, nitro, acetyl, —CF₃, —SCF₃ andcyano.
 16. A compound as claimed in claim 5, wherein the point ofattachment of the group Y to the O or S atom is attachment at the 7position.
 17. A compound as claimed in claim 5, wherein the point ofattachment of the group Y to the O or S atom is attachment at the 4position.
 18. A compound as claimed in claim 5 , wherein Y is quinolyl,isoquinolyl or naphthyridyl, each of which may be optionally substitutedwith up to 5 substituents each independently selected from halo, C₁-C₄alkyl, C₁-C₄ alkoxy, C₁-C₄ alkyl-S(O)_(n)— where n is 0, 1 or 2, nitro,acetyl, —CF₃, —SCF₃ and cyano.
 19. A compound as claimed in claim 18,wherein the point of attachment of the group 10 Y to the O or S atom isattachment at the 4 position.
 20. A compound as claimed in claim 18,wherein the point of attachment of the group Y to the O or S atom isattachment at the 5 position.
 21. A compound as claimed in claim 18,wherein the point of attachment of the group Y to the O or S atom isattachment at the 6 position.
 22. A pharmaceutical compositioncomprising a compound of formula I or a pharmaceutically acceptable saltthereof, as defined in claim 1, together with a pharmaceuticallyacceptable diluent or carrier.
 23. A compound of formula I or apharmaceutically acceptable salt thereof, as defined in claims 1, foruse as a pharmaceutical.
 24. A compound of formula I or apharmaceutically acceptable salt thereof, as defined in claim 1, for useas a selective inhibitor of the reuptake of both serotonin andnorepinephrine.
 25. A compound of formula I or a pharmaceuticallyacceptable salt thereof, as defined in claim 1, for use in the treatmentof a disorder associated with serotonin and norepinephrine dysfunctionin mammals.
 26. A compound of formula I or a pharmaceutically acceptablesalt thereof, as defined in claim 1, for use in the treatment of adisorder selected from selected from depression, OCD, anxiety, memoryloss, urinary incontinence, conduct disorders, ADHD, obesity,alcoholism, smoking cessation, hot flushes/flashes and pain. 27-32.(canceled)
 33. A method for treating disorders associated with serotoninand norepinephrine dysfunction in mammals, comprising administering to apatient in need thereof an effective amount of a compound of formula Ior a pharmaceutically acceptable salt thereof, as defined in claim 1.34. A method as claimed in claim 33, wherein the disorder is selectedfrom depression, OCD, anxiety, memory loss, urinary incontinence,conduct disorders, ADHD, obesity, alcoholism, smoking cessation, hotflushes/flashes and pain.
 35. A method as claimed in claim 33 or 34,wherein the disorder is pain.